When assessing the biological equivalence of generic drugs, it is established. Pharmaceutical, biological and therapeutic equivalence. Requirements for drugs

For quotation: Meredith P.A. Replacement of original medications with generics: bioequivalence and therapeutic equivalence of various amlodipine salts // RMZh. 2009. No. 18. S. 1150

According to the definition, a generic is a medicine whose prescription of the active substance is not protected by a patent and/or exclusive right. To confirm the fact of interchangeability of an innovative brand and a generic, it is necessary to establish their bioequivalence. In the pharmaceutical market, generic drugs are quite competitive. But even if they are bioequivalent, these substances may differ from registered drugs, and their use is associated with a number of potentially significant aspects. The following review provides evidence regarding hypothetical differences between generic and brand-name drugs and their implications for clinical practice. As an example, we consider the calcium channel antagonist amlodipine, a drug for the treatment of cardiovascular diseases, for example, hypertension and angina, which is used in the form of two salts: besylate (Norvasc, Istin and Amlor *) and maleate (some gene -ricky).
Methods
A search of the literature scientific databases Med-line and EMBASE was carried out in August 2008 without restrictions on publication date. The search parameters were full-text articles in English containing both keywords (amlodipine, bioavailability, stability, toxicity, generics, therapeutic equivalence) and text-independent terms (amlodipine besilate, amlodipine maleate, equivalence, guidelines, salts). In addition, the bibliography of the list of references was also analyzed. Search results for bioequivalence and therapeutic equivalence were not considered as a basis for the systematic review. Nevertheless, the review below can still be considered systematic, since it includes all available scientific data on amlodipine maleate (within the given limitations). Information is also provided from leading European and American websites dedicated to this issue.
Terminology of concepts
"equivalence" and "similarity"
Despite some differences in wording, experts from both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) define the concepts of “pharmaceutical alternative” and “pharmaceutical equivalence” in a similar way (Table 1). Generic drugs - alternative or equivalent - have the same composition of active ingredients as the original drug. However, they may differ from it in shape, size, color, configuration of notches (scores) on a flat surface, release mechanism (immediate, modified, etc.), excipients (dyes, fragrances, preservatives, binders, fillers , lubricants, disintegrating agents, etc.), by production method, expiration date, type of packaging and, with some restrictions, labeling. Various compositions of excipients are allowed, which are supposed to be inert, but the generic must have the same ratio of active and auxiliary components as the original drug.
By definition, bioequivalence means the absence of a significant difference between drugs in the rate and extent of absorption (i.e., bioavailability) when used in the same molar dose (Table 1). Bioequivalent drugs are considered "substantially similar" as recognized by the FDA. They “have the same qualitative and quantitative composition (meaning the content of active ingredients), dosage form and are bioequivalent to the extent that scientific research has not proven that the drug with a medical prescription differs from the original one in its effectiveness and safety” . Paradoxically, the EALS guidelines contain two interpretations of therapeutic equivalence (Table 1): pharmaceutically equivalent drugs are considered therapeutically equivalent if they have proven bioequivalence, but in the case of pharmaceutically alternative drugs, additional (pre)clinical studies may be required data that would allow us to speak about their therapeutic equivalence.
All these terms are reflected in the legal requirements for the use of generic medicines. If we are talking about pharmaceutically equivalent drugs, then the abbreviated procedure for registration of new drugs (ANDA) is applicable to them. When submitting an ANDA, the sponsor must provide evidence of bioequivalence between the pharmaceutically equivalent generic and the brand-name drug (Figure 1), which are determined to be therapeutically equivalent. Unlike a new drug application (NDA), which has high quality requirements, an ANDA does not necessarily require clinical safety and efficacy data (Figure 1).
Evaluation and criteria
bioequivalence
Although different countries use different methods for assessing bioequivalence, the World Health Organization (WHO) guidelines provide a general recommendation to include at least 12 clinically healthy adult volunteers aged 18-55 years of normal weight in a crossover study. body. In practice, bioequivalence is studied in randomized, crossover, two-stage studies in groups of 18-24 clinically healthy and relatively young volunteers. Typically, a single dose of a generic or original drug is taken under standard conditions (taking into account the type of diet, amount of fluid consumed, level of physical activity and time of taking the drug). To minimize variability between subjects, standard samples are formed and standardized protocols are used, as a result of which any deviations that occur that go beyond the statistically acceptable limits can be attributed to differences in prescriptions, and not to the individual characteristics of the subjects. Moreover, the data obtained suggest that the assessment of systemic release of the active component is more sensitive when studies are conducted with a single dose rather than multiple doses. Because concomitant ingestion of food and oral medications may affect bioequivalence, it is recommended (in the case of long-acting medications) or even required (in the case of drug-food interactions) to perform additional testing of the ingredients included in the standardized food set.
The pharmacokinetic effects of drugs are assessed and statistically analyzed using parameters such as the area under the plasma concentration versus time curve (AUC) and the maximum plasma concentration (Cmax). These indicators allow the most accurate determination of the extent and rate of absorption of the drug (i.e., bioavailability) and its exposure, terminal half-life (t 1/2), elimination rate constant (λ Z) and - in specific circumstances - rate of urinary excretion ( AC). We can talk about bioequivalence if the 90% confidence interval (CI) of AUC and Cmax for the generic/original drug ratio is between 0.80 and 1.25. Since the data is logarithmized for comparison, an asymmetry arises, called the -20%/+25% rule. However, for critical dose drugs that have a narrow therapeutic index (i.e., a small difference between the minimum effective concentration and the minimum toxic concentration) - immunosuppressants, antiepileptics, cardiac glycosides (digoxin), anticoagulants (warfarin) - the limits of these values ​​are reduced . This is due to the fact that even relatively small fluctuations in the systemic level of such drugs can provoke a noticeable change in pharmacodynamics, namely their effectiveness or the incidence of side effects. For drugs with high intrasubject variability (>30%) and little toxicity at Cmax, the EA (but not the FDA) allows the 90% CI for Cmax to be extended to 0.75 to 1.33. The need to evaluate tmax to establish bioequivalence is determined by regulatory laws. This is partly due to the lack of uniform statistical methods for analyzing tmax - a value that (unlike the continuous variables AUC and Cmax) is discrete and depends on the sampling plan specified by the protocol. Thus, unlike the FDA, the EMA requires that tmax be determined only when there is clinically significant indication of rapid release/onset of action or when evidence of an adverse effect occurs.
Disagreement on the issue
interchangeability
EALS does not make any clear recommendations regarding the interchangeability of bioequivalent medicines. According to the FDA, in the United States, about 20% of generic drugs are not bioequivalent to registered brand names, and therefore these drugs cannot be considered interchangeable. But paradoxically, FDA experts point out that there is no documented evidence that a specific generic cannot replace the corresponding patented original drug. Thus, doctors do not have to worry if a patient refuses the original drug and switches to a generic drug (or changes from one generic drug to another).
However, given the differences in the terminology of bioequivalence and approaches to its assessment, as well as in the criteria for therapeutic equivalence (which raises the question of the therapeutic effectiveness of the drug), it seems appropriate to consider various aspects of interchangeability.
Evidence of research
by bioequivalence
Typically, the results of bioequivalence studies are used by health care organizations to develop regulations, but are rarely published. Typically, these data are freely available on relevant websites or can be obtained through the Freedom of Information Act (if they are US research data), but partially restricted access still precludes their easy analysis and verification by the general scientific community.
Conclusions about the bioequivalence of certain drugs are based mainly on the results of relatively small fixed-dose trials in clinically healthy volunteers. Consequently, such studies do not achieve equilibrium drug concentrations. But in the case of most chronic diseases, to achieve a therapeutic effect, it is necessary not only to achieve such a concentration of the drug, but also to maintain it for a long time. If the patient is on maintenance therapy, the level of the drug in his blood is usually higher than after taking a single dose (sometimes several times). Thus, in studies involving clinically healthy volunteers, the data obtained do not reflect real-life situations observed in clinical practice. This may cause certain difficulties, since it is possible that during maintenance therapy the pharmacokinetics of the drug changes under the influence of hypothetically inert excipients (excipients) and impurities and/or as a result of the accumulation of active metabolites. In addition, the characteristics of a homogeneous group of clinically healthy volunteers and a sample of patients are likely to differ (in the latter case, older individuals with different comorbidities, taking a variety of medications for hypertension and/or coronary heart disease), and therefore extrapolate the data it is forbidden . The pharmacokinetics of the drug may also change due to the physiological processes of aging, as a result of interaction with drugs used simultaneously and/or due to the presence of concomitant diseases. Therefore, the effects of a drug in a healthy person cannot be compared with the effects of the same drug in everyday clinical practice. Typical examples are procaine hydrochloride, the degree of absorption of which is statistically significantly different in clinically healthy individuals and patients with acute myocardial infarction, and generic verapamil, which is bioequivalent to the original product only in young and clinically healthy people, but not in elderly patients.
Further, equivalence values ​​ranging from 0.8 to 1.25 are also criticized, because theoretically, the rate and/or extent of absorption of the compared drugs may actually differ by 20% (Fig. 2). For drugs with a registered trade name, the standards are much stricter (5%) and for drugs with a narrow therapeutic index the requirements are simplified. Subtle differences in bioavailability become important when the drug is poorly soluble in water, has nonlinear kinetics and/or a modified release profile.
There is also a more fundamental problem related to the fact that truly bioequivalent drugs have the same effect on a particular patient (i.e., they are therapeutically equivalent). But in practice, it is not possible to determine this, since bioequivalence studies analyze average values ​​for generics and original products, reflecting the average equivalence in terms of bioavailability. However, this is not enough to judge how interchangeable the drugs are. The results obtained using other approaches - population or individual - can be considered more reliable: they allow one to assess not only the average bioequivalence, but also the equality in the distribution of bioavailability within and between subjects. However, regulatory authorities do not sanction the use of alternative approaches and their implementation is allowed only in special situations.
Regulatory norms concepts
"therapeutic equivalence"
Speaking about therapeutic equivalence, which is established by bioequivalence, it should be noted that the identity of the excipients is not a strictly necessary condition. However, the composition of the latter plays an important role in ensuring the stability and preservation of the appearance of the product, and therefore differences in the content of excipients may cause a discrepancy between the therapeutic effect and the safety/tolerance profile. In addition, the shelf life of tablet forms of drugs depends on the characteristics of their production process (level of compression pressure, use of rotating or other machines, etc.). Most bioequivalence studies are unlikely to take these aspects into account.
It is well known that in terms of treatment outcomes, not all drugs of the same therapeutic class are interchangeable, and this may be due to a number of factors. Generic and original products are no exception in this case. Thus, all antihypertensive drugs are registered on the basis that they reduce blood pressure (BP). When reducing blood pressure by a specific amount, these drugs are expected to have a similar effect on fixed endpoints, reducing the risk of (non)fatal stroke, MI, or heart failure. But if the generic contains, for example, a different salt of the active ingredient, then this assumption may not be correct. Therefore, to establish the interchangeability of medicinal substances, it is more appropriate to directly compare them over a long period of time, considering the frequency of occurrence of certain clinical events as the primary end point. While this does not apply to all generics, it should be emphasized that they are much more likely to benefit from regulatory guidelines for biologically similar drugs (i.e., biologics, generics, and biotechnology-derived medicinal products) rather than current guidelines. According to the EALS guidelines for these substances, (pre)clinical trials must be carried out before registration on the pharmaceutical market.
Salt of the active ingredient
as a key factor
Alternative salts of patented drugs are considered by the EMA and the FDA as new chemical entities. And yet, the procedure for registering such drugs is significantly simplified due to previous (clinical) experience with the use of other salts. If it is reliably established that the pharmacokinetics, pharmacodynamics and/or toxicity of the active substance of a drug containing another type of salt do not change (and these factors can affect the effectiveness and/or safety of the drug), then the abbreviated 505b application procedure is applicable (2), or hybrid NDA.
Approximately half of the active ingredients of drugs for therapeutic use are salts (rather than free acids or bases). The synthesis of alternative types of salts of drugs is a method of optimizing their physicochemical properties - such as solubility, hygroscopicity, (thermo) stability, solubility, fluidity, degradation mechanism - without changing the structure. But these same properties determine the extent to which the drug is retained in the body, and therefore, the form of the salt can affect its biological characteristics (i.e. pharmacokinetics and pharmacodynamics) and clinical effectiveness. Currently, there are no reliable methods that would allow us to accurately predict how a change in the type of salt will affect the state of the active substance.
In order to be able to submit an ANDA containing bioequivalence information and obtain official registration in the pharmaceutical market before the patent of the original product expires, pharmaceutical companies often use other types of salts when producing generic drugs. Such generics should not automatically be considered a pharmaceutical equivalent of the original drug; rather, they should be considered as a pharmaceutical alternative, i.e. chemical derivative of the active substance. It logically follows from this that the therapeutic equivalence of such generics cannot be judged only on the basis of bioequivalence data, and additional preclinical and clinical trials are necessary for their widespread implementation in practice.
Effect on absorption
tolerability and safety
Another factor that affects the bioavailability of a drug due to changes in its solubility is solid-state polymorphism. It is defined as the ability of a substance to maintain a strictly ordered conformation and/or molecular arrangement when in a crystalline state.
Salts vary in their solubility in water and dissolution rate. These characteristics determine the degree of absorption of the drug in vivo, and therefore its pharmacokinetics and biological properties. This once again demonstrates the need to conduct bioequivalence studies, although issues of drug tolerability and safety are not always considered in them. For example, conjugated cations or anions of salt-forming agents can react with salts, thereby causing a toxic effect. These data were obtained from preclinical trials of pravadoline maleate, whose nephrotoxicity was shown to be due to the formation of maleic acid. Changing the type of salt can have other unpredictable consequences. Thus, disruption of the gastrointestinal tract due to the use of certain salts of al-pre-nolol, detected in experimental animals in the esophageal test, is associated with an increase in its solubility. Finally, drug interactions may also be disrupted: it has been established that the anesthetic substance propoxyphene hydrochloride destabilizes acetylsalicylic acid.
Impact on stability
and optimal writing
The hygroscopicity and hydrophobicity of the salt partly determines the stability of the active substance of the drug, especially if it is easily hydrolyzed. In the case of a low melting point of the salt, plastic deformation of the drug occurs, followed by hardening or aggregation of the active substance. As a result, the dosage of the drug ceases to be universal, and other characteristics of the solid dosage form deteriorate, which negatively affects the industrial production process.
Biologically active impurities
Chemical impurities that appear during the synthesis of a particular drug or due to its instability can provoke toxic phenomena during its use. Therefore, the content of impurities should not exceed the permissible standards prescribed in the regulatory documents of the International Conference on the Harmonization of Technical Requirements for Registration of Medicines Used in Humans.
The instability of the drug due to changes in the salt form can be demonstrated using the example of amlodipine maleate (Fig. 3). Unlike besylate (Fig. 3), maleate undergoes degradation, which results in the formation of chemical impurities. One such reaction is the addition of the primary amine group of amlodipine to unsaturated maleic acid. This side reaction occurs both at the stage of synthesis of the salt of the active substance of the drug, and during the production and storage of finished products. When studying the stability of experimental pharmacological prescriptions, it was found that the content of impurities can reach 2%. It is not clear whether this has any clinical significance, but it is certain that the biological activity of these impurities does not correspond to the characteristics of amlodipine. The results of ligand and enzymatic analysis of purified (>99%) degradation products (100 nM) indicate a wide range of molecular and tissue effects mediated by them, including impairment of contractility of isolated cardiac muscle.
Further, when conducting high-performance liquid chromatography, 6 types of impurities were detected in the composition of amlodipine maleate in amounts ranging from 0.43 to 1.42%. In tablets of amlodipine maleate (but not besylate), two main degradation products were identified, which once again confirms the hypothesis of a different stability profile of these medicinal compounds. Thus, the inherent instability of amlodipine maleate, which causes the appearance of impurities (i.e., biologically active degradation products) in the finished dosage form, does not allow us to speak of the equivalence of the maleic and besylate salts of amlodipine.
Impurities and degradation products as a result of changes in the salt form of the active component can potentially have a genotoxic effect. A separate guideline on genotoxic impurities has recently been issued by the EMA Committee on Medicinal Products for Clinical Use. It presents a general scheme and practical recommendations on how to neutralize the effect of genotoxic impurities that are contained in drugs synthesized on the basis of new active ingredients. In the USA, Canada and Japan there are no such guidelines, and solutions to the problem have not yet been found.
Amlodipine besylate and amlodipine maleate: brief information
Clinical data on amlodipine besylate
The mechanism of action of amlodipine, a dihydropyridine calcium antagonist, is to relax the smooth muscle cells of the vascular wall and reduce peripheral vascular resistance, resulting in a decrease in systemic blood pressure. Due to its ability to cause dilatation of peripheral and coronary vessels, it stops an attack of angina, which is also partly due to a decrease in myocardial oxygen demand and a drop in the tone of the coronary vessels (i.e., relieving their spasm). All this together causes the restoration of coronary blood flow.
In 1992, Pfizer released amlodipine besylate in tablet form for administration once a day (dosage 2.5-5-10 mg), registering it under the trade names Norvasc (USA and most European countries), Eastin (Great Britain, Ireland) and Amlor (Belgium, France). Indications for prescribing amlodipine are arterial hypertension, chronic stable angina and vasospastic angina (Prinzmetal or variant).
The clinical profile of amlodipine was actively studied both at the stage of its development and after registration. Particular attention was paid to its pharmacological properties, as well as long-term safety and efficacy (with analysis of fixed endpoints). Almost all data on the safety and effectiveness of amlodipine concern its besylate salt. A recently completed meta-analysis suggests that amlodipine besylate is more effective than other antihypertensive drugs and placebo in preventing stroke as a cardiovascular disease (hazard ratio 0.81, p<0,0001 и 0,63 при p=0,06, соответственно) . Лечение амлодипина безилатом также значительно уменьшает риск ИМ, как одного из исходов . Этим данным можно доверять, поскольку они были получены в выборке численностью более 78 тыс. человек, которые участвовали в двух крупных исследовани-ях - ALLHAT и ASCOT . В целом же информационная база по опыту клинического применения амлодипина малеата включает результаты примерно 800 клинических испытаний, в которых участвовало более 600 тыс. пациентов, подвергавшихся рандомизации .
Amlodipine besylate and amlodipine maleate
In most European countries, the patent for amlodipine expired in 2004, in the USA it was extended until 2007. In addition to the original brand, which is protected by a patent, in many European countries (Germany, Sweden, UK, etc.), in Korea and South In Africa, generic drugs containing amlodipine maleate as the active ingredient have also appeared. Since 2007, generic versions of amlodipine besylate have become available worldwide.
The maleic acid salt was initially used in the production of amlodipine, but was later abandoned for a number of reasons, including the inherent instability of the drug substance and problems with tablet forming. It is also necessary to take into account information about the nephrotoxic effect of maleic acid in rodents. Subsequently, the presence of toxic effects of both maleic acid and pravadoline maleate was confirmed in other studies (see above). Thus, doubts about the safety of commercial prescriptions of amlodipine maleate in humans are not unfounded, which forced a number of clinical trials to be conducted before its widespread use in practice.
Only a few studies have compared the bioequivalence of amlodipine maleate, and only one has published the results. There is freely available data on the effectiveness and safety of amlodipine maleate for essential hypertension, but not for stable angina.
An open-label, randomized, two-stage crossover study in a group of 24 clinically healthy volunteers (age 24-45 years) examined whether a single dose of amlodipine maleate (Omicron Pharma) was bioequivalent to Norvasc/amlodipine besylate (Pfizer). Since there was no statistically significant difference between these substances in terms of AUC and Cmax, and the CI limits for amlodipine maleate (Table 2) were within the limits allowed by the EALS (for Cmax 0.75-1.33), it was concluded about their bioequivalence. Apparently, in clinical practice, both salts are interchangeable, since the kinetics of amlodipine maleate in blood plasma is determined only by the properties of the molecule itself. However, in the United States, these dosage forms will not be considered interchangeable due to the fact that the requirements for drugs with high variability are stricter here.
Given the fact that the steady-state concentration of amlodipine in the blood should be much higher, and hypertension is more likely to develop in old age (amlodipine pharmacokinetics have been shown to change in such people), there is a strong argument for the need to assess bioequivalence in studies involving elderly patients by prescribing medications in multiple doses.
The efficacy and safety of amlodipine besilate and amlodipine maleate were analyzed in two multicenter randomized controlled trials. The first was conducted over 8 weeks in South Korea (n=118), its purpose was a comparative study of Norvasc (Pfizer) and amlodipine maleate (manufacturer unknown). The second study began as double-blind (for 3 months) and then continued as open-label (for 6 months); Polish scientists evaluated Norvasc (Pfizer) and Tenox (Krka, Slovenia) in a group of 250 people. Both studies included patients with stage 2-3 arterial hypertension. Initially, for two weeks, the medications previously taken by the subjects were discontinued, and then amlodipine besylate or amlodipine maleate was prescribed at a dose of 5-10 mg 1 time per day. According to the results of a Korean study, according to a prespecified criterion (change in diastolic blood pressure by 4 mm Hg), the effectiveness of amlodipine maleate did not exceed that of amlodipine besylate (Fig. 4). However, the choice of this value was arbitrary and not supported by clearly established regulatory standards, and the available epidemiological data suggest that such fluctuations in diastolic blood pressure may affect cardiovascular outcomes: if the results of 61 cohort studies and 147 randomized trials are meta-analyzed, it turns out that change in diastolic blood pressure by 4 mm Hg. causes a difference in the incidence of coronary heart disease by 20%, and stroke by 29%. Moreover, during therapy with amlodipine besylate, a slightly larger number of patients were able to control blood pressure compared with the use of amlodipine maleate (92 and 86%, respectively). It became possible to talk about the comparable effectiveness of both drugs as antihypertensives after 3 months, during which the study was conducted in Poland (Fig. 4A). Although in the last 6 months there was a statistically significant increase in blood pressure by 0.9 mm Hg. in the group receiving amlodipine maleate (p<0,01 для диастолического АД и p<0,05 для систолического АД), значимого подъема уровня АД по сравнению с исходными величинами не отмечалось (рис. 4А) . Оба препарата имеют сходный профиль безопасности (рис. 4Б) , но следует учесть, что это данные только за первые 3 месяца .
The lack of a statistically significant difference in the results of both studies allowed their authors to conclude that amlodipine maleate can be considered as an alternative to amlodipine besylate. However, one should not make hasty generalizations and say that these drugs are interchangeable, because these studies do not clearly define inclusion and exclusion criteria, the sample size is limited, and there are no long-term results (>3 months). To speak about the therapeutic equivalence of drugs in terms of their antihypertensive effect, trials are required in cohorts of at least 600 people lasting at least 6 months. The key goal of treatment with antihypertensive drugs is to influence fixed endpoints (ie, reduce the incidence of stroke and MI), so the best solution when studying therapeutic equivalence is to conduct large-scale, longitudinal clinical trials with direct comparison of effects. One of these long-term (approximately 4.4 years) studies had a randomized, double-blind, placebo-controlled design. But the published report contains data only on the cumulative incidence of major cardiovascular events in all antihypertensive treatment groups compared with placebo, which precludes the possibility of independent evaluation of amlodipine maleate. It also needs to be determined whether amlodipine maleate is therapeutically equivalent to amlodipine besylate as an antianginal agent.
Conclusion
Despite the fact that the terminology of concepts such as bioequivalence and therapeutic equivalence was defined several decades ago, there is still debate about the interchangeability of generics and original drugs. Bioequivalence, as European and American experts point out, implies, but does not guarantee, the presence of therapeutic equivalence. This may be due to a number of reasons, including: with variations in bioequivalence allowed for generics and the predominant evaluation of these drugs only in short-term studies involving a small number of young and clinically healthy individuals. More importantly, the lack of data from clinical trials with fixed endpoints that would demonstrate the long-term efficacy and safety of generics calls into question the relevance of the current criteria in general, since the patient is exposed to some risk.
Although generics and original medicines must contain the same active ingredients, have the same route of administration, have the same strength, quality, degree of purity and pharmacological identity, they may differ, for example, in the composition of impurities that should be inert, but are not necessarily so. In addition, despite the possibility of a simplified application for registration of a drug that contains a different form of salt, changing the type of salt can affect the profile of the drug, as evidenced by many observations (for example, the original brand amlodipine besylate and generic amlodipine maleate). Although both formulations have been shown to be bioequivalent by definition, to date they have not been directly compared in real clinical settings over the long term. Moreover, unjustified prescribing of amlodipine maleate should be avoided due to the (potential) nephrotoxicity of maleic acid/maleates in animals and/or the presence of biologically active impurities in the drug resulting from the destruction of the active substance or other processes. It is necessary to conduct a number of studies in order to speak with complete confidence about the therapeutic interchangeability of amlodipine besylate and maleic salts.

* Norvasc, Istin and Amlor are registered trade
Pfizer brand names

Abstract prepared by Ph.D. E.B. Tretiak
based on materials from an article by P.A. Meredith
"Potential concerns about generic substitution: bioequivalence versus therapeutic equivalence
of different amlodipine salt forms"
Current Medical Research and Opinion 2009;
Vol. 25, No. 9: 2179-2189

Therapeutic equivalence of a generic drug and how to prove it.

N.P.Kutishenko1, S.Yu.Martsevich1,2, I.V.Vashurina1
1FGU GNITS PM Ministry of Health and Social Development of Russia, Moscow
2Department of Evidence-Based Medicine, First Moscow State Medical University. I.M.Sechenova

The problem of the effectiveness and safety of copy drugs (reproduced drugs, generics) continues to worry scientists, doctors, and the public. It is constantly addressed at scientific conferences and symposia, in the media, special scientific studies are devoted to it, which sometimes involve thousands of patients, for example, the ORIGINAL study (Evaluating the effectiveness of transferring from Indapamide Generics to Arifon Retard in patients with Arterial Hypertension). And all this despite the fact that the scientific part of this problem has largely been solved long ago in numerous studies, and its practical part is reflected in a number of regulatory documents, which will be discussed below. It is characteristic that in foreign scientific literature there are now extremely rare publications devoted to the comparative assessment of original drugs and generics, although quite recently there were much more such publications.

Of course, certain uncertainties remain regarding the effectiveness and safety of some generics, however, in our opinion, they primarily reflect problems with meeting the necessary conditions that, according to modern concepts, ensure the therapeutic equivalence of a generic drug.

The purpose of this publication is precisely to recall the basic principles for assessing the therapeutic equivalence of generic drugs.

What is a generic (reproduced drug)

Strange as it may seem, there is still no single definition of the concept of “generic”: WHO (World Health Organization), FDA (Food and Drug Administration), EMEA (European Medicines Agency), ministries of health of various countries offer their definitions for reproduction drug, as well as criteria on the basis of which a generic can be considered therapeutically equivalent to the original drug. In general, these criteria coincide, however, there are certain differences in assessing the significance and necessity of conducting therapeutic equivalence studies to prove the compliance of the generic with the original drug both in terms of effectiveness and safety.

Without a doubt, the most clear, thoughtful and scientifically based system for assessing the equivalence of generic drugs today exists in the United States, which is reflected in FDA documents. As defined by the FDA, therapeutic equivalence is established through pharmaceutical equivalence and bioequivalence studies. If there is no doubt about equivalence, then the drug is assigned an appropriate code starting with the letter “A”, which also means that it can be considered as a possible reference drug (i.e. comparator drug). If the bioequivalence data does not exclude potential doubts regarding the therapeutic equivalence of pharmaceutically equivalent drugs, or bioequivalence studies have not been conducted (for example, for topical drugs), then the therapeutic equivalence assessment code begins with the letter “B”. Most generic drugs under this coding system are typically coded "AB" - this means that differences between drugs are potentially possible, but equivalence is supported by the results of adequately performed in vitro and/or in vivo studies. It should be noted that special clinical studies confirming the therapeutic equivalence of the original drug and the generic are not expected.

WHO defines the therapeutic equivalence of the original drug and the generic (multi-source pharmaceutical product) somewhat differently. According to WHO requirements, two pharmaceutical products are considered therapeutically equivalent if they are pharmaceutically equivalent (or pharmaceutically alternative) and, after administration at the same molar dose, their effect in terms of efficacy and safety is exactly the same for the same route of administration and for the same indication. This must be demonstrated through appropriate bioequivalence studies, such as pharmacokinetic, pharmacodynamic, clinical or in vitro studies.

From the point of view of EMEA (European Medicines Agency), bioequivalence studies are necessary not only to demonstrate the similarity between the generic and the original drug in terms of basic pharmacokinetic parameters. Such studies provide a real opportunity to transfer data on the effectiveness and safety obtained for the original drug to the generic, while therapeutic equivalence studies are not expected (with the exception of biological drugs).

The Russian Federal Law “On the Circulation of Medicines” introduces the concept of a generic medicinal product, but is somewhat in conflict with documents from other countries. In accordance with the Federal Law of the Russian Federation dated April 12, 2010 N 61-FZ, "when conducting the examination procedure for generic drugs (these include generics), information obtained during clinical trials of drugs and published in specialized printed publications, as well as documents containing the results of bioequivalence and (or) therapeutic equivalence studies. If we talk about studies of therapeutic equivalence of drugs, then this term refers to a type of clinical trial, which is carried out to identify the same properties of drugs of a certain dosage form, as well as the presence of the same indicators of safety and effectiveness of drugs, the same clinical effects when used.

Regarding the issue of confirming therapeutic equivalence, there are certain contradictions with FDA regulations, and there are no documents defining the procedure for conducting and criteria for assessing the results of such clinical trials. If we turn to the time-tested FDA rules for determining therapeutic equivalence, then five conditions must be met: 1) the drugs must be recognized as effective and safe, 2) they must be pharmaceutically equivalent, including consistency in the amount of active ingredients, their purity, quality, identity, 3) meet bioequivalence standards with at least 24-36 volunteers participating in the study, 4) correctly labeled and, just as important, 5) manufactured in accordance with GMP (Good Manufacturing Practice) requirements.

Significance of therapeutic equivalence studies

However, despite the importance of bioequivalence indicators when registering a generic drug, the results of clinical studies to prove equivalence remain of some importance. To a greater extent, this applies to analogues of pharmaceuticals of biological origin (so-called biosimilars or biogenerics). For them, therapeutic equivalence studies are one of the conditions for registration. In the near future, such drugs will increasingly appear on the pharmaceutical market, since patents for a number of original biological products (including low molecular weight heparins) are expiring. In this regard, some generic companies have begun to develop the production of biosimilars, despite the fact that the chemical structure and technology for producing biosimilars are much more complex than traditional chemical drugs. Since biosimilars have a complex three-dimensional spatial structure, their quantitative content in biological fluids is quite difficult to accurately characterize, so it is generally accepted that for such drugs conventional bioequivalence studies are clearly insufficient. This forces regulatory authorities to require biosimilar manufacturers to conduct both preclinical (toxicological, pharmacokinetic and pharmacodynamic) and clinical studies (full reporting of drug efficacy and safety data), as well as immunogenicity data. Biological drugs include hormones, cytokines, blood clotting factors, monoclonal antibodies, enzymes, vaccines and drugs created on the basis of cells and tissues, etc.

"Generic replacement"

It should be noted that differences in the therapeutic effect of original drugs and generics or different generics among themselves are, in principle, allowed by a number of international documents. Quite a long time ago, the term “generic replacement” was introduced, which refers to the dispensing of a drug whose commercial name differs from that prescribed by a doctor, but the chemical composition and dosage of the active principle is identical. The documents of the World Medical Assembly warn that when dispensing drugs that are not completely identical in chemical composition, biological action or therapeutic effectiveness, the patient may experience an inadequate effect, i.e. with adverse reactions or insufficient therapeutic efficacy. This document draws special attention to the fact that government control services must inform doctors about the degree of chemical, biological and therapeutic identity of drugs produced by the same or different manufacturers, and quality control services existing at drug manufacturing enterprises are required to monitor the continued conformity of products drugs to standards of chemical and biological properties.

The question arises why, despite the established methods of monitoring generics, there are often those on the market that clearly do not fully correspond to the original drugs either in terms of effectiveness or safety, and sometimes in both respects. This situation, unfortunately, is quite typical for our country. There is no final answer to this question yet, but I think the main thing is the violation of the very principles of preclinical evaluation of generics that were mentioned above. It is well known that in Russia the GMP standard is still not observed in the production of most of the drugs produced in our country (it is believed that the transition of all Russian drug manufacturers to the GMP quality standard should occur only by January 2014), and this alone creates a good reason for obtaining generics that are of inadequate quality.

What should a practitioner consider when choosing generic drugs?

A simpler question also arises: what should practitioners do when choosing a drug, especially in cases where this therapy is long-term and the quality of which may determine the fate of the patient, for example, in the secondary prevention of cardiovascular complications in high-risk cardiac patients. On the one hand, all regulatory documents, as well as economic feasibility, force the doctor to use the generic first (if it is registered). On the other hand, a number of well-designed clinical studies (uncontrolled studies do not count) indicate that not all generics are full copies. These facts are skillfully used by pharmaceutical companies, claiming that all generics are inferior drugs and, by using them, the doctor is knowingly prescribing less effective therapy.

Most Russian specialists, recognizing the facts stated above, conclude that it is necessary to conduct direct comparative studies to study therapeutic equivalence with those generics that are already registered and most often prescribed in the clinic. The Department of Preventive Pharmacology of the Federal State Institution State Scientific Research Center for PM has attempted to create a register of clinical controlled randomized trials, performed with generics in Russia.

Thus, on the one hand, there is no reason to doubt that the creation of a generic - a complete copy of the original drug - is absolutely possible. However, certain deviations in the development and production of a generic drug may affect its quality. Ideally, these deviations should be recorded by the entire preclinical control system, but in practice, apparently, this system is not always strictly followed, which leads to the emergence of incompletely equivalent generics. In such cases, the only way to confirm the quality of a generic drug is to conduct methodically well-planned comparative clinical trials to study therapeutic equivalence. The results of such studies will also make it possible to more accurately answer the question of the rationality of the intervention, both from the point of view of economic efficiency and its accessibility.

Bibliography

1. Martsevich S.Yu. Copies of medicines, like copies in art, come in different forms. AIF. Health 2010; 4:2-3.
2. Martsevich S.Yu. Replacement tablets. What is the difference between cheap medicines and expensive ones? AIF. Health 2011, 8: 35.
3. Karpov Yu.A., Nedogoda S.V., Kislyak O.A., Deev A.D. etc. Main results of the ORIGINAL program. Cardiology 2011; 3: 36-41.
4. Johnston A, Staylas P, Stergiou G. Effectiveness, safety and cost of drug substitution in hypertension. Br J Clin Pharmacol 70:3; 320-334.
5. www.Guideline on similar biological medicinal products (CHMP/437/04
6. World Medical Association Statement on Generic Drug Substitution Adopted by the 41st World Medical Assembly Hong Kong, September 1989 and rescinded at the WMA General Assembly, Santiago 2005
7. Recommendations of the All-Russian Scientific Committee “Rational pharmacotherapy of patients with cardiovascular diseases.” In the working group: Martsevich S.Yu., Anichkov D.A., Belolipetskaya V.G., Kontsevaya A.V., Kutishenko N.P., Lukina Yu.V., Tolpygina S.N., Shilova E. V., Yakusevich V.V. Cardiovasc ter profile 2009; 6: Appendix 4: 56 p.
8. Yakusevich V.V. A quality medicine: what it should be. Rational pharmacotherapy in cardiology 2006; 4: 41-46.
9. Revelsky I.A. A method for comparative physiological assessment of pharmaceutical substances and preparations based on them. Bulletin of Roszdravnadzor 2009; 4: 48-51.
10. Martsevich S.Yu., Kutishenko N.P., Deev A.D. Original drugs and generics in cardiology. Is it possible to solve the problem of interchangeability? Bulletin of Roszdravnadzor 2009; 4: 48-51.

Pharmaceutical equivalence

Drugs are pharmaceutically equivalent if they contain the same active substances in the same amount and in the same dosage form, meet the same or similar standards, and are identical in potency or concentration of the active substances. Often, despite the same content of active substance, a generic drug differs from the original in the composition of excipients

Composition of the original drug Vigamox and generic Moxicin in terms of 5 ml of solution

• Vigamox (28)
• Moxicin (29)

Active ingredient: oxyfloxacin hydrochloride 0.02725 g moxifloxacin hydrochloride 0.02725 g

Preservative benzalkonium chloride

Other excipients sodium chloride sodium chloride

boric acid

hydrochloric acid and/or sodium hydroxide (to adjust pH)

water for injections

Generic moxifloxacin hydrochloride contains a preservative; the original drug Vigamox does not contain a preservative.

Bioequivalence

Two drugs are considered bioequivalent if they are pharmaceutically equivalent, have the same bioavailability and, when administered at the same dose, are similar, providing adequate efficacy and safety. Bioavailability refers to the rate and proportion of absorption of the active ingredient or active component of a drug that begins to act at the point of application.

In essence, bioequivalence is the equivalence of the rate and extent of absorption of the original and the generic at the same concentration doses in body fluids and tissues. The reliability of the results of a comparative bioequivalence study largely depends on compliance with the requirements (GMP - good clinical practice) and should be independent, multicenter, randomized, controlled, long-term.

If a generic drug is approved for use in other countries, it is registered in the Russian Federation according to a simplified scheme (without determining bioequivalence). Thus, when registering foreign generics in the Russian Federation, we largely trust the dossiers submitted by pharmaceutical companies. Such “gullibility” in some cases costs patients dearly, because Generics may not correspond to the original drug in their pharmacokinetic properties. Using the example of a control check of the bioequivalence of generics to the original clarithromycin C.N. Nightingale et al compared the original clarithromycin product with 40 copies for bioequivalence using American Pharmacopoeia standards. The study showed that 70% of generics dissolve much more slowly than the original drug, which is critical for their absorption. 80% of generics differ from the original in the amount of active ingredient in one unit of the product. The amount of impurities not related to the active principle is greater in most samples than in the original. In the “best” generic there were 2% of them, in the “worst” - 32%. The presence of impurities determined the severity of adverse reactions.

Ophthalmologists also face a similar situation. Congdon N.G. et al. (2001), based on the results of a randomized, double-blind study, established a predominance of cases of irritation of the conjunctiva and cornea in connection with the local use of a generic NSAID - diclofenac, compared with patients receiving a brand-name drug.

The ultimate goal of drug policy in any country in the world is to provide the population with safe, effective, high-quality and affordable medications. One of the key points in this policy is the widespread use of generic drugs.

Yu.S. Rudyk, Institute of Therapy named after L.T. Small Academy of Medical Sciences of Ukraine, Kharkov

Most often, generics are used for socially significant diseases that have a high prevalence (arterial hypertension, chronic heart failure, tuberculosis, diabetes, etc.). In this regard, it is obvious that a beneficial effect on the course and outcome of socially significant diseases can be achieved only by using relatively affordable and high-quality generics.

According to the WHO definition, the term “generic” is understood as a drug used in medical practice interchangeably with an innovative (original) drug, produced, as a rule, without a license from the creator company and sold after the expiration of the patent or other exclusive rights.

A generic drug must meet the following criteria:

• contain the same active ingredient as the original drug;
• have similar bioavailability;
• produced in the same dosage form;
• maintain quality, effectiveness and safety;
• do not have patent protection;
• have a lower cost compared to the original drug;
• comply with pharmacopoeial requirements, produced under GMP (good manufacturing practice) conditions;
• have the same indications for use and precautions.

As clinical practice shows, drugs containing the same active ingredients in the same pharmaceutical forms and doses, but produced at different enterprises, can differ significantly both in therapeutic effectiveness and in the frequency of adverse reactions provided for in the instructions for their medical use.

EU Directive 2001/83 also defines essentially similar products. A medicinal product is essentially similar to the original drug if it meets the criteria of the same quantitative and qualitative composition with respect to active substances, the same dosage form and is bioequivalent, unless it is scientifically obvious that it differs from the original drug regarding safety and effectiveness.

One of the main issues for both the doctor and the patient is the problem of interchangeability of generic and original drugs.

The international community and national health services are interested in the development and implementation of scientifically based criteria for assessing the effectiveness and safety of generic drugs produced by various companies.

According to modern concepts, the conformity of a generic and a brand-name drug is based on three important components, referred to as pharmaceutical, pharmacokinetic and therapeutic equivalence.

In European countries, it is believed that drugs are pharmaceutically equivalent, if they contain similar active substances in the same quantity and in the same dosage form, they meet the requirements of the same or similar standards.

By American definition, pharmaceutically equivalent drugs contain the same active ingredients in the same dosage form, are intended for the same route of administration, and are identical in potency or concentration of the active substances.

But pharmaceutically equivalent agents will not necessarily be therapeutically equivalent, i.e. those, after application of which in the same molar dose, the effect in terms of effectiveness and safety is virtually the same. Thus, erythromycin, registered in the Russian Federation, when administered intravenously with a high frequency caused thrombotic complications, while in European countries Abbott's erythromycin is widely used for intravenous administration, being considered the safest macrolide antibiotic for intravenous infusion.

Excipients play an important role in the safety of drug use. When creating generic drugs, it is necessary to require the preservation of the original composition of the excipients, which, however, is not always known. The use of auxiliary ingredients in generic drugs is regulated based on WHO recommendations.

When assessing pharmacokinetic equivalence (or bioequivalence) The features of absorption and distribution of drugs in the human body are compared. According to the WHO definition, “two medicinal products are considered bioequivalent if they are pharmaceutically equivalent, have the same bioavailability and, when prescribed at the same dose, provide adequate efficacy and safety.”

The definitions adopted in the European Union (EU) and the United States are slightly different.

According to the European formulation, two medicinal products are bioequivalent if they are pharmaceutically equivalent or alternative and if their bioavailability (rate and extent of absorption) after administration at the same molar dose is similar to such an extent that their effectiveness and safety are essentially the same.

According to the American definition, bioequivalent drugs are pharmaceutically equivalent or pharmaceutically alternative drugs that have comparable bioavailability when studied under similar experimental conditions.

A bioequivalence study is essentially (for orally administered drugs) a comparative bioavailability test. For each drug under study, the main pharmacokinetic parameters characterizing the completeness of absorption must be determined: the area under the concentration-time curve (AUC), the rate of absorption (C max, T max) and the rate of elimination of the active substance (K el, T 1/2) . To conclude that there are no differences in these parameters, analysis of variance is used and 90% confidence intervals are calculated. To confirm equivalence, it is required that the 90% confidence intervals of the ratios of the bioavailability parameters of the test drug do not go beyond -80 and +125% of the reference drug.

It is important to note that it is impossible to talk about the bioequivalence of drugs if it is not known for sure where and how the drug was produced. If there is no confidence that the manufacturing site where the drug is produced complies with GMP requirements, there is no point in pursuing bioequivalence studies, like other clinical trials, because the quality of the drugs is not maintained from batch to batch. In a global sense, GMP is a step-by-step, systematic, step-by-step “incorporation” of quality into a drug. In this regard, bioequivalence research is only part of the overall system for ensuring the quality of medicines.

All generics must have proven bioequivalence, since theoretically only bioequivalent drugs can have similar clinical efficacy and safety profile.

In 1984, the US President signed a law requiring the FDA (Food and Drug Administration) to make publicly available a list of approved prescription and over-the-counter drugs. This law introduced for the first time the new assumption that bioequivalent drugs are therapeutically equivalent and therefore interchangeable. Edition “Approved Drug Products with Therapeutic Equivalence Evaluations”- a list that is commonly called "Orange Book", - identifies drugs approved by the FDA based on their safety and effectiveness. Speaking about the status of the Orange Book, it should be noted that by informing its assessment of the therapeutic equivalence of drugs using the list, the FDA offers its recommendations to the public, specialists and authorized bodies on drug selection. Such an assessment should not be considered as a prohibition on the use of a particular drug or as evidence that one is preferable to another. The Orange Book mainly serves not to differentiate multisource drugs from each other, but to inform whether, using the available tools, the problem of proving their therapeutic equivalence to the reference drug has been resolved or not. Therapeutic equivalence is a scientific judgment, while the practice of generic substitution, aimed at cost savings, is also based on social and economic aspects.

The appearance of the Orange Book is due to the fact that in order to save money in the healthcare system, almost all US states have passed laws and/or regulations that encourage the implementation of generic substitution. The implementation of these laws required the creation of a positive or negative list of drugs (those that either can or cannot replace the original drug). FDA specialists created a single drug formulary in which the assessment of therapeutic equivalence of drugs was presented in the form of a letter code. The system of letter codes describing therapeutic equivalence allows you to quickly determine whether a certain drug is bioequivalent to the reference drug (first letter) and obtain additional information about the FDA assessment (second letter). The two main categories into which generic drugs can be classified are designated A and B. Category A includes drugs that are therapeutically equivalent to other pharmaceutically equivalent products, for which:

• no known or suspected bioequivalence issues; they are designated by the letters AA, AN, AO, AP or AT depending on the dosage form;
• actual or potential bioequivalence problems can be resolved by adequate evidence of bioequivalence; in such cases, the designation AB is used.

Code B denotes drugs that the FDA currently considers to be not therapeutically equivalent to other pharmaceutically equivalent products, i.e., actual or potential bioequivalence issues cannot be resolved by adequate determination of bioequivalence. Often the problem lies with the specific dosage form rather than the active ingredient. In such cases, the designations BC, BD, BE, BN, BP, BR, BS, BT, BX or B are used.

At one time, the FDA published draft guidance on the activities of pharmaceutical companies, as well as enterprises that were owned or influenced by distributors (so-called sponsors) of medical products. The need for public hearings and discussion of the project was due to the fact that individuals and groups of people contacted state legislative bodies, pharmaceutical organizations, and drug control committees, expressing concerns about the problem of interchangeability of some drugs, in particular drugs with limited therapeutic index. They were especially interested in whether the safety and effectiveness of such drugs would change if, instead of a drug from a well-known manufacturer, they began to use a drug recognized by the FDA as therapeutically equivalent, but not protected by a registered trademark. A letter from FDA Commissioner for Health Affairs Stuart L. Nightingale was published in 1998 clarifying this topic. Below is his summary: “Based on the determination of therapeutic equivalence of drugs, the FDA made the following statement:

• additional clinical tests are not required when replacing a drug from a well-known company with a product with an unregistered trademark;
• There is no need to take special precautions when changing the formulation or manufacturing process of a drug, provided that the changes are approved by the FDA in accordance with FDA laws and regulations;
• as stated in the Orange Book, in the FDA's opinion, drugs determined to be therapeutically equivalent can be expected to have the same clinical effect regardless of whether the drug is known or new;
• there is no need to treat any class of drugs differently from another class if the FDA has determined therapeutic equivalence for the drugs in question.”

According to the FDA, therapeutically equivalent Drugs that meet the following general requirements are considered:

a) their effectiveness and safety have been proven;

b) they are pharmaceutically equivalent, namely:

• contain the same amount of identical active ingredients in the same dosage form and are intended for the same route of administration;
• meet the requirements for potency, quality, purity and identity;

c) are bioequivalent, namely:

• there are no known or potential bioequivalence issues and they meet the in vitro or
• if existing known or potential problems can be eliminated by conducting bioequivalence studies;

d) adequate instructions in the instructions;

e) manufactured in accordance with GMP requirements.

According to the WHO definition, two drugs are considered therapeutically equivalent if they are pharmaceutically equivalent, have the same bioavailability of the drug substance and, when administered at the same molar dose, provide adequate efficacy and safety.

Thus, therapeutic equivalence is a basic requirement for the interchangeability of drugs.

Determining the bioequivalence of drugs is the main criterion for medical and biological quality control of generic drugs, adopted for the EU countries, USA, Russian Federation, etc.

It is believed that if the bioequivalence of drugs is proven, there is no need to conduct additional clinical trials of generic drugs, since the presence of bioequivalence indicates that all indicators of the effectiveness and safety of the drug under study are comparable. Bioequivalence trials are clinical studies involving healthy volunteers or patients who are eligible for the drug under investigation.

Assessment of the bioequivalence of generic drugs is strictly regulated by relevant international and national standards. Currently, in Ukraine, due to the intensive expansion of the pharmaceutical market, competition among analogues of medicines of various manufacturers is increasing. The bioequivalence of many of them (especially for domestic drugs) has not been proven. Clinical trials conducted on a limited program of these drugs cannot always provide sufficiently objective information about their effectiveness and safety.

WHO guidelines for determining the interchangeability of similar drugs available from different sources (so-called multisource drugs) note that Bioequivalence is most often used to confirm therapeutic equivalence. At the same time, it is also possible other approaches, namely:

1. comparative determination of pharmacodynamic characteristics (eg, pupil dilation, changes in heart rate or blood pressure), when the pharmacodynamic response is easier to measure or more reliable than pharmacokinetic parameters, or for topical drugs;
2. limited comparative clinical trials where neither pharmacokinetic nor pharmacodynamic studies provide convincing evidence;
3. in vitro tests, for example, determining the solubility of a dosage form (dissolution test), including in the form of a solubility profile established at several points.

Finally, in some cases, specific evidence of therapeutic equivalence is not required, for example, provided that all chemical (eg, impurity profile), pharmaceutical (eg, stability) and manufacturing (GMP) characteristics correspond to those of the selected standard. In other words, it is believed that in these cases the conformity of the technical parameters alone guarantees therapeutic equivalence. In all cases, we are talking about comparative trials with drugs whose therapeutic effectiveness is considered proven.

Based on the above, it is obvious that therapeutic equivalence includes pharmaceutical equivalence and one of the criteria:

• bioequivalence studies in humans;
• pharmacodynamics study in humans;
• clinical trials;
• in vitro dissolution test (in some cases).

The production and quality control of generics also depends on excipients. The requirements for them must be the same as for the active substance. Any change in the composition of the excipients or the drug shell can significantly change the quality of the drug, its bioavailability, and lead to toxic or allergic phenomena.

The concept of therapeutic equivalence applies only to medicinal products containing the same active ingredients and does not apply to different therapeutic drugs used in the same clinical situations (for example, paracetamol and acetylsalicylic acid prescribed for headaches).

A medicinal product that meets the above criteria for therapeutic equivalence is considered as such, even if it differs in certain characteristics, such as the form, tablet mark, packaging, excipients (including dyes, preservatives), shelf life and minimal differences in instructions (for example, the presence of specific information on pharmacokinetics), as well as storage conditions. If such differences are important in the treatment of a particular patient, the doctor may require that a specific brand be dispensed from the pharmacy. Apart from this limitation, the FDA believes that drugs classified as therapeutically equivalent may be substituted with the full expectation that the substitution will maintain the effects and safety profile expected of the prescribed drug.

We must admit that In both the EU and the US, many experts question pharmacokinetic equivalence as the only way to assess the interchangeability of drugs. A number of publications point out significant methodological shortcomings in studying the bioequivalence of drugs, which can lead to the fact that existing differences between brand and generic drugs will not be identified. According to European requirements and FDA regulations, individual pharmacokinetics may differ by up to 20%. It is believed that fluctuations in the concentration of the active component in the blood plasma in the range from -20 to +25% are not clinically significant, however, for elderly patients or other vulnerable groups of patients, even such minor changes in the concentration of the drug substance may increase the risk of side effects.

It is assumed, for example, that certain limitations may be associated with the existence of drugs characterized by a relatively small spread in therapeutic concentrations of the drug in the blood plasma (some antidepressants - paroxetine, fluoxetine, citalopram) and/or non-linear pharmacokinetics (normotimics and antiepileptic drugs).

In this situation, even small changes in this parameter, well within the acceptable limits of the bioequivalence test (from -20 to +25%), may be significant for clinical effectiveness and/or tolerability.

Hence, There may be significant differences in the properties of branded and generic medicines. For example, if bioequivalence is below 100%, the drug may be ineffective. On the contrary, with an increase in the considered indicator, an increase in the number of side effects should be expected. Of particular concern are drugs with a low therapeutic index (the difference between the minimum effective dose of a drug and its maximum toxic dose) - digoxin, phenytoin, carbamazepine, cyclosporine, warfarin. This situation requires tightening and expanding the requirements for pharmacokinetic studies. The issue of reducing differences in parameters to 10-15% is being discussed, which will reduce the number of drugs with borderline pharmacokinetic parameters.

Another limitation is imposed on the use of bioequivalence test results by the existence of drugs (sertraline, fluoxetine, chlorpromazine, clozapine) with significant variability in pharmacokinetic parameters, which depends, in particular, on the complexity of the drug’s metabolic processes (cytochrome system, the presence of several elimination routes, etc. .). Such variability may be of an “intra-individual” nature. In one case, it is associated, for example, with the genetic polymorphism of cytochromes, which is observed in different populations, in the other, with the functional state of these enzymes, which changes in the same person under the influence of various external factors (for example, drinking grapefruit juice). Therefore, the results of a bioequivalence test performed on a small group of volunteers consuming a similar diet may not be valid in real-world clinical settings.

The tendency to use a single daily dose of drugs during bioequivalence studies is also critical.

It is known that many drugs (amiodarone, digitalis drugs, psychotropic drugs) are prescribed repeatedly over a certain period of time and to obtain a clinical effect, it is necessary to achieve a stable (therapeutic) concentration of the drug in the blood plasma and/or tissue, which can be significantly higher than that used when conducting bioequivalence studies on healthy volunteers.

It should also be borne in mind that in real clinical practice, generic drugs are taken for a long time by patients of different ages, gender, body weight, often suffering from comorbid (concomitant) pathology. In such a situation, the pharmacokinetic properties of branded and generic drugs, due to the existence of even small chemical differences between them, can differ significantly. The pathology of the gastrointestinal tract acquires a certain importance. In patients with this disease, the rather complex mechanism of drug absorption is easily disrupted. Moreover, even minor differences in the chemical composition of branded and generic drugs can lead to a violation of their bioequivalence.

In particular, a situation may arise when inert compounds (excipients) used in generics, when prescribed in a single dose, without affecting the absorption, distribution and metabolism of drugs, with long-term use can affect the functional state of the gastrointestinal tract, liver or kidneys in such a way that the pharmacokinetic equivalence of the drugs is significantly impaired.

As an example, we can cite the various compositions of excipients of original and generic nicergoline preparations, widely used by patients of different ages, including elderly patients, often suffering from a wide range of concomitant diseases of internal organs.

Another problem is associated with the presence of concomitant somatic pathology, which significantly complicates the clinical use of the results of the bioequivalence test. Unlike healthy volunteers, patients with concomitant pathologies are often forced to take various somatotropic drugs, in particular those that enhance or weaken peristalsis, affecting the destruction of the drug in the intestine. It is possible that this effect, due to the existing, albeit minimal, differences in the chemical composition of the original and generic drugs, may be ambiguous. Accordingly, conditions arise for changing the bioequivalence of these drugs.

The objections discussed are not merely theoretical considerations. The relevant publications contain a lot of information about the results of cross-checking the bioequivalence of various drugs. These data suggest that a significant proportion of generic drugs fail such testing. Thus, conducted in Great Britain in 1995-1996. analysis of 2427 generic drugs found 228 significant differences. No less striking data were obtained in the USA. The FDA has found that up to 20% of brand-name and generic drugs available nationwide are not bioequivalent and therefore cannot be used interchangeably.

Examples of clinical non-equivalence of enalapril drugs are given. It was shown that the clinical effectiveness of 4 generic enalaprils from well-known manufacturers in achieving the target blood pressure level in patients with arterial hypertension was lower than that of the original drug (Renitek, MSD). The generics studied were pharmacokinetically equivalent to Renitec. Based on the results obtained, the authors concluded that the generic enalapril preparations are unequal in therapeutic equivalence.

The therapeutic non-equivalence of the original indapamide (Arifon, Servier) and its generics in patients with arterial hypertension was reported by V.I. Petrov et al. , while the pharmacokinetic profiles of the compared drugs were the same.

Equivalence of generics is of particular importance for antimicrobial drugs, since low antimicrobial activity can lead to a decrease in the clinical effectiveness of therapy, which is especially important when treating seriously ill patients, and the rapid spread of resistant forms of microbes. A recent study of the mycological activity of original fluconazole (Diflucan, Pfizer) and generic drugs showed that the activity of generics against various species of fungi of the genus Candida is 2 times lower than that of Diflucan. At the same time, generics were bioequivalent to the original drug.

One of the publications provides data from a comparative analysis of the quality of the original clarithromycin produced by Abbott and 40 of its generics from 13 countries in Asia and Latin America. It turned out that in 8 drugs the content of the active substance did not meet the standards of the developer company; in 28 generics, the amount of the active component released upon dissolution was significantly lower than that of the original, although all of them had the appropriate specification. Twenty-four of the 40 drugs exceeded Abbott's recommended 3% limit for contaminants.

The amount of particulate matter in 4 generic cefotaxime preparations was increased 10-fold compared to the original drug (Claforan, Hoechst). These particles contained in generics can disrupt microcirculation in ischemic tissues and contribute to the development of respiratory distress syndrome and multiple organ failure in severe patients.

The literature presents comparisons between branded and generic clozapine (Clozaril, Novartis Pharmaceuticals and clozapine, Zenith Goldline Pharmeceuticals). The study found that a discrepancy between these psychotropic drugs in pharmacokinetic parameters is observed in 40% of patients suffering from schizophrenia.

Significant differences in bioequivalence were identified between branded drugs amitriptyline hydrochloride, nortriptyline hydrochloride, desipramine, trimipramine maleate and their generics.

More than 100 studies have been conducted on the bioequivalence of various generics of phenytoin and valproic acid preparations, in which significant differences were found in the pharmacokinetic parameters of original and generic drugs.

Speaking about therapeutic equivalence, we should mention a study by R. Mofsen et al., which describes 7 cases of unsuccessful replacement of brand-name clozapine with its generic in patients with a stable mental state who were in a psychoneurological boarding school. It is emphasized that this change in therapy was unexpectedly made by the pharmacy and neither the doctors nor the medical staff of the institution knew about it. They were completely surprised by the resumption of psychotic disorders in patients, the severity of which in 5 out of 7 cases required urgent measures to transfer the patients to a psychiatric hospital. A similar case has been reported when switching from brand-name paroxetine (Paxil) to its generic version.

A recent survey of neurologists (301 respondents) working in the United States found that when switching from brand-name antiepileptic drugs to generics, 204 (67.8%) of them observed a resumption of seizures, 168 (55.8%) noted an increase in side effects .

11 cases are described in which, after replacing brand-name lamotrigine with generics, control over epileptic seizures was lost.

As a result of these studies, a number of countries, including Norway, have adopted decisions limiting the transfer of patients from branded antiepileptic drugs to generic drugs, and in Germany this procedure is not recommended at all.

A number of controlled studies have shown that when switching from brand-name carbamazepine to generic carbamazepine, there is a sudden return of seizures.

Another paper, published in the American Journal of Cardiology in May 2000, cited 64 expert electrophysiologists, members of the North American Paced Electrophysiology Society, who reported 32 cases of recurrent arrhythmias (ventricular fibrillation, ventricular tachycardia, atrial fibrillation, and atrial tachycardia) during replacing the branded antiarrhythmic drug amiodarone (Cordarone, Sanofi-Synthelabo) with its generics.

It should be noted that there are also publications on the therapeutic equivalence of original and generic drugs. One randomized, double-blind study examined two parallel groups of outpatients with chronic schizophrenia treated with brand-name fluphenazine decanoate. The first group was switched to its generic, the second group was left on the original drug. After 12 weeks, in both groups there was no significant dynamics in the condition, determined by a special scale of positive and negative syndrome.

Speaking about chronic diseases, it should be noted that many of them tend to recur. In view of this, modern recommendations provide for long-term maintenance therapy along with relief therapy. In practice, there is often a situation where relief therapy, most often carried out in a hospital, is carried out with an original drug. Subsequently, after the patient is discharged, this drug is often replaced with its generic version for “economic” reasons. In light of the data presented above, it is obvious that the replacement under consideration is possible only if there is confidence in the pharmaceutical, pharmacokinetic and therapeutic equivalence of the original and generic drugs.

There are reports that the appearance of generic drugs on the pharmaceutical market does not always lead to a reduction in direct healthcare costs. A recent Canadian study found that the 11% difference in relapse rates observed between generic and brand-name clozapine negated the cost advantage of the generic. Similar data have been obtained for antiepileptic drugs.

The given data, like many others, according to the chief clinical pharmacologist of the Ministry of Health of the Russian Federation, Professor Yu.B. Belousov, dispel the myth that generics are cheap, since the costs of using them are much higher than when using original drugs. Contrary to popular claims that generic drugs reduce direct treatment costs, promote competition and lower prices for brand-name drugs, and are even a way to introduce cost-effective medical technologies into clinical practice, some modern research suggests the opposite.

The scientist believes that the transition from inexpensive generics to original drugs is beneficial both for patients and for society as a whole. He believes that it is unacceptable to transfer data on effectiveness and safety obtained on original drugs to their copies. Only the availability of complete information on compliance with GMP requirements in the production of a generic, its pharmacokinetic and therapeutic equivalence when compared with the original drug, makes the search for pharmacoeconomic advantages of a generic justified. Otherwise, formally favorable price indicators can result in huge additional costs, for example, for the treatment of unwanted side effects. According to Yu.B. Belousov, the practice that has developed in the Russian Federation, allowing the medical use of a generic drug based only on its bioequivalence, is incorrect. To determine therapeutic equivalence, it is necessary to conduct both limited and large clinical studies of the effectiveness of a generic drug in a specific disease, studying the comparative effectiveness of the original and generic drugs using clear endpoints. Therapeutic equivalence also means organizing studies of the safety profile of generics with intensive monitoring for 5 years after registration of undesirable effects.

It is obvious that original drugs will always be opposed to generic ones, but their competition in the pharmaceutical market should be based on strict compliance with the requirements for the quality of production of both original and generic drugs, on the results of bioequivalence tests, as well as clinical trial data. Therefore, the widespread use of generic drugs in clinical practice should be based on clear indications available to practicing physicians regarding their pharmaceutical, pharmacokinetic and, above all, therapeutic equivalence to the original drugs.

The list of references is in the editorial office

Routes of administration of medicinal substances allow us to approach the definition of such a concept as bioequivalence. It makes sense to determine it only for drugs that have a systemic effect. The problem of bioequivalence is closely related to the emergence of generic drugs. As an analysis of the pharmaceutical market in many countries has shown, a significant part of the turnover is not original products, but their cheaper copies or analogues (the so-called generic forms, or generics). In the USA, generics account for more than 12% of drug sales; in Western European countries this figure ranges from 30 to 60%, in Russia - up to 90%83.
One of the first laws regulating the production of generic drugs can be considered the law adopted in 1938 in the USA53. The first modern definition of this term was proposed in France in 1986. Generics were understood as “copies of the original drug, the production and marketing of which are possible after the expiration of the patent protecting the innovative drug”84. Later, a clarification was introduced: “A drug from a specific manufacturer that is substantially similar to the original product, presented in the same dosage form and having the same qualitative and quantitative composition of active ingredients and bioequivalence as the original product”85.
However, it is obvious that these requirements in some cases may be insufficient to determine the therapeutic equivalence of two drugs.
One of the common definitions of the concept “generic” is that it is a drug registered on the basis of an incomplete dossier (set of registration documents). In other words, in world practice, generics in the vast majority of cases are not tested in the clinic. In the recent past, permission for their use was carried out on the basis of the assumption: “If the composition and dosage form of the reproduced drug are very similar to those of the original, then the therapeutic properties should also be similar.” However, over time, the requirements related to confirming the therapeutic equivalence of generic drugs with their innovative analogues have become more stringent, i.e. drugs that have undergone clinical evaluation. The following types of equivalence are distinguished:

• Pharmaceutical - complete reproduction by a generic drug of the composition and dosage form of the original drug. Moreover, drugs that have pharmaceutical equivalence may have different bioavailability, i.e. therapeutic effects.
• Pharmacokinetic (bioequivalence) - similarity of pharmacokinetic parameters.

• Therapeutic - the effectiveness and safety of the generic drug in pharmacotherapy are similar to the original drug.

• Original drugs produced by well-known pharmaceutical companies are manufactured in accordance with Good Medical Practices (GMP) requirements; they have generally undergone extensive clinical trials. Compliance with GMP requirements can be difficult to establish for generic drugs, and clinical trials for these drugs are rare.
• The cost of raw materials for generic drugs is about 50% of the production cost, which can prompt unscrupulous manufacturers to search for cheaper (and lower quality) raw materials. Additional material costs in the production of generic drugs may be associated with geographic distance from manufacturers of high-quality raw materials.
• When creating generic drugs, it is necessary to require the preservation of the original composition of excipients, which, however, is not always known. The use of excipients in generic drugs is regulated based on the recommendations of the World Health Organization87, 88.

• quality;
• efficiency;
• safety.

the formulation is not sufficient, since it does not take into account the time to reach maximum concentration or the rate of elimination of drugs. A more stringent definition is given by the WHO: “Two pharmaceutical products are bioequivalent if they are pharmaceutically equivalent and their bioavailability parameters (rate and degree of availability) after administration at the same molar dose are similar to such an extent that their effects can be expected to be substantially the same.” Similar requirements are imposed by the FDA, with bioequivalence tested using a non-model method directly from pharmacokinetic curves (Fig. 1.31); The following parameters are considered95:

• AUC0-t is the area under the pharmacokinetic curve from the moment of administration of the pharmacological drug to time t;
• AUC0-™ - area under the pharmacokinetic curve from the moment of administration of the pharmacological drug to the time

• the value of the maximum concentration St,^ and the time of its achievement T^^;
• bioavailability, calculated as the ratio of the areas under the pharmacokinetic curves (see Fig. 1.9).

Rice. 1.31. Examples of bioequivalent (a) and non-bioequivalent (b) pharmacokinetic curves for the original drug (1) and generic (2)
As follows from the above requirements, not only the intake, but also the excretion of the pharmacological drug is taken into account.
The FDA's bioequivalence guidelines place great emphasis on study design. The design is carried out in a double-blind, pairwise comparison AB/BA crossover design. Both the effect of a single injection of the drug and the effect of long-term therapy are being studied.
WHO guidelines for determining the interchangeability of similar drugs available from different sources (so-called multisource drugs) note that bioequivalence is most often used to confirm therapeutic equivalence. At the same time, other approaches are also possible.

yes. In particular, this may involve comparative determination of pharmacodynamic characteristics (i.e. pharmacological properties, e.g. pupil dilation, changes in heart rate or blood pressure), limited comparative clinical trials, in vitro tests, for example, determination of the solubility of the dosage form ( dissolution test), including in the form of a solubility profile established at several points. However, the consistency of the results obtained in vitro and in vivo is determined to a lesser extent by the solubility of drugs in water and to a greater extent by their permeability through the wall of the small intestine (Table 1.22), therefore there is a “gold standard” of substances whose permeability is good studied (Table 1.23).
Table 1.22. Correlation of biopharmaceutical parameters in in vitro and in vivo experiments for drugs with immediate release of the active substance

Table 1.23. Ending

Permeability

Propanolol

Internal standard

Theophylline

Class IV (Table 1.22)

Specific evidence of therapeutic equivalence is not required if all chemical (e.g. impurity profile), pharmaceutical (e.g. stability) and manufacturing characteristics are consistent with those of the selected reference standard. In other words, it is believed that the conformity of technical parameters in itself guarantees therapeutic equivalence.
Note that we are talking about comparative tests with drugs whose therapeutic value is considered proven. In this regard, the question arises about the choice of a reference drug, otherwise a standard, or “comparator” in WHO terminology. It is generally accepted that comparison of the bioequivalence of a generic drug should be made with the original product. However, the problem is that for drugs that have been introduced for a long time, it can be difficult to determine which “brand” was the first to enter the world market. In some cases, the innovative drug is known but has ceased to be produced, and therefore its samples are effectively unavailable for use in comparative trials. There may be several reasons for this situation: sales or exchange of patents, mergers of pharmaceutical companies, informal agreements between companies on the division of market segments, etc.
Taking this into account, alternative approaches to the selection of standards are widely used. They often focus on a drug of a given series, which was the first to be registered in any country (and not in the world), or on an analogue that has received the widest recognition among doctors and patients (the so-called market leader). It is clear that with this approach, the choice of standards may be different in different countries. In addition, both the first registered drug and the market leader in a particular country may themselves be generics. This situation is especially typical for former socialist countries. In these cases, the registration of new generics resembles photocopying from copies, which, as is known, leads to the appearance of texts or drawings that are less and less similar to the original. Based on these considerations, much work has been done within WHO to identify originator products that can be used as the “gold standard” for determining bioequivalence61,96.
In 1999, the first version of the list of comparators, containing almost 300 items, was discussed at a meeting of the WHO expert committee, was approved by it and included with the necessary explanations.

additions to the text of the final document. The list is divided into two parts almost equal in volume. The first of them (list A*) contains the recommended comparators. The second part (list B) is the remainder, including drugs for which reference “brands” could not be found, for example, tablets of digoxin, reserpine, phenobarbital, as well as drugs for which special evidence of equivalence may not be required (paracetamol, chloroquine, etc. .). The list of comparators (i.e. List A) has been published in the WHO bulletin68.
The second part of the list (list B) will appear as an annex to the report of the expert committee. It should be emphasized that in the process of using WHO recommendations in this area, the second part of the list (list B) plays no less important role than the first, as can be seen from the decision-making diagram on the choice of a reference drug.

The problem of bioequivalence is closely related to the emergence of generic drugs. To compare generic drugs with original ones, their pharmacokinetic equivalence or bioequivalence is studied.
This study includes the determination of several parameters that reflect the processes of absorption, distribution and excretion from the body of the compared drugs:

1. values ​​of areas under pharmacokinetic curves;
2. their relationship;
3. the value of the maximum concentration of the drug and the time to reach it.

• Has nothing to do with pharmacy lists of poisonous and potent drugs.