When assessing the biological equivalence of generic drugs, it is established. Generics and drug equivalence. Reasons for incomplete bioequivalence
3.5.1. BASIC CONCEPTS
Closely related to the concept of bioavailability is the concept of bioequivalence. Two drugs are considered bioequivalent if they provide the same bioavailability of the drug substance after administration at the same dose and in the same dosage form.
According to WHO (1994, 1996) and EU (1992) regulations, differences in pharmacokinetic parameters for bioequivalent drugs should not exceed 20%.
Currently, the study of bioequivalence is the main type of biomedical quality control of generic drugs. The introduction of bioequivalence determination as a method makes it possible to make an informed conclusion about the quality, effectiveness and safety of compared drugs based on a smaller amount of primary information and in a shorter time than during clinical trials.
Today, there are regulations for studying bioequivalence of WHO (1996), EU (1992), Russian Federation (1995, 2000). They set out the main rationale for conducting bioequivalence studies. These studies must be carried out if there is a risk of lack of bioequivalence or a risk of reducing the pharmacotherapeutic effect and clinical safety of the drug.
For example, drugs for the treatment of conditions for which a guaranteed therapeutic effect is required are necessarily evaluated; drugs with a small therapeutic breadth; drugs whose pharmacokinetics are complicated by a decrease in absorption of less than 70% or with high elimination (more than 79%); drugs with unsatisfactory physicochemical properties (low solubility, instability, polymorphism); drugs with documented evidence of a bioavailability problem.
Bioequivalence studies (pharmacokinetic equivalence) should in no way be considered as an alternative to pharmaceutical equivalence tests - the equivalence of generic drugs in terms of the qualitative and quantitative composition of drugs, assessed by pharmacopoeial tests, since pharmaceutical equivalence does not guarantee pharmacokinetic equivalence. At the same time, bioequivalence studies suggest that generic drugs that are bioequivalent to the original provide the same effectiveness and safety of pharmacotherapy, that is, they are therapeutic equivalents.
The assessment of bioequivalence is based on the results of studying the relative bioavailability of the drug substance in the compared drugs. By their essence, bioequivalence studies are a special type of pharmacokinetic study. First of all, it must be emphasized that bioequivalence studies are clinical trials where the subject of the study is a human. Therefore, such studies are subject to all the same official requirements and regulations as all other clinical trials. A team of specialists of various profiles should plan and conduct studies to determine bioequivalence: clinical pharmacologists, clinicians, biochemists, and analytical chemists. Bioequivalence studies must be conducted in full compliance with the principles of Good Clinical Practice (GLP) to ensure the quality of the data presented and to protect the rights, health and well-being of study subjects.
Bioequivalence studies in animals are not widely accepted and are rarely used. They are used only at the stage of preclinical research or in the case of studying drugs intended for use in veterinary medicine. As a rule, the term “bioequivalence” in this case is replaced by the term “pharmacokinetic equivalence”.
When determining the equivalence of antimicrobial drugs, it is possible to use in vitro methods, however, in this case, the term “bioequivalence” is preferred not to be used.
Currently, Ukraine has a sufficient material and technical base, highly effective methods are used to determine pharmacokinetic parameters, and specialists are trained in the field of bioequivalence studies, which makes it possible to solve the urgent problem of assessing the effectiveness and safety of generic drugs of domestic and foreign production.
3.5.2. OBJECTS OF RESEARCH
BIOEQUIVALENCE
The objects of bioequivalence studies are generic drugs intended for extravascular administration (oral, sublingual, etc.), provided that the effect of these drugs is mediated by the appearance of the drug in the systemic circulation. As a comparison drug, you should use the corresponding original drug or its analogue, which has found widespread medical use (preferably one that is produced under license from the authors of the original drug).
In some cases, confirmation of equivalence is not required. For example, for pharmaceutical analogues of approved systemic agents in the form of solutions - injection solutions, solutions for external use, eye drops.
For drugs to which the concept of bioavailability does not apply (non-systemic drugs - external, ophthalmic, vaginal, etc.), it is recommended to conduct comparative clinical or pharmacodynamic studies.
3.5.3. SUBJECT CONTINGENT
WHEN STUDYING BIOEQUIVALENCE
Considering the fact that bioavailability parameters can be significantly influenced by individual anatomical and physiological characteristics, the population studied in the study of bioequivalence should be as homogeneous as possible. To reduce the spread of data obtained, drug trials are conducted on healthy volunteers. Persons of both sexes between the ages of 18 and 55 are eligible. The body weight of the subjects should not exceed 20% of the age physiological norm for a given gender. It is preferable that the subjects be non-smokers. Before starting research, it is necessary to conduct a thorough history taking, as well as examine subjects using standard laboratory tests to exclude persons with impaired function of the eliminating organs (liver, kidneys) and cardiovascular system. Before and during testing, special medical examinations can be carried out, the need for which is determined by the peculiarities of the pharmacological properties of the drug being studied.
In some cases, instead of healthy volunteers, patients with certain diseases are included in the study group. This situation may arise if the drug being studied has known side effects and the health of volunteers could be seriously harmed (for example, studying drugs used in oncology, in the treatment of HIV infection, etc.).
The minimum number of subjects required for a bioequivalence study is 12 people. A bank of volunteers who meet the above criteria is formed taking into account the candidates’ participation in other research and donation. The minimum interval between participation in other studies and donation is 3 months. All volunteers must be informed about the purpose and procedure of the test, which is documented in a special “Informed Consent”.
The planning and conduct of the study should be based on knowledge of the pharmacokinetics and pharmacodynamics of the drug being studied.
2 weeks before the start of the test, volunteers are invited to re-collect anamnesis. If, in the period preceding the conversation, a volunteer suffered any diseases that could affect the results of the study, he is not included in the group of subjects.
During preparation for the study, backups are also selected in case of unexpected replacement of volunteers who dropped out of the study. The number of backups is 25% of the number of volunteers.
Standard conditions must be created for all subjects, namely:
> food and water regime (standard diet for 1 day before the study and throughout its duration);
> complete exclusion of taking any other medications for 2 days before taking the study;
expected drugs and during the pharmacokinetic study;
> avoiding the use of alcohol, caffeine, drugs, concentrated juices;
> standard motor mode and daily routine.
The health status of volunteers, their compliance with the regime,
The organization of nutrition, the correct selection of blood samples and their processing are controlled by clinical researchers.
Bioequivalence studies are carried out with one dosage (preferably the highest) of a given generic drug in a given dosage form, even if it is declared for registration in several dosages. In the case of long-acting dosage forms, bioequivalence should be checked for each dose separately. Assessment of bioequivalence can be based both on data obtained from a single administration of drugs, and from their repeated (course) use. In the latter case, it is necessary that the subjects receive the drugs in the same single dose with the same dosing interval (in accordance with the instructions for medical use of the drug) until a steady state is achieved.
A feature of the design of bioequivalence studies is that each of the subjects receives both the study drug and the comparison drug. When selecting volunteers into groups, preference is given to the crossover method with randomized distribution of volunteers.
The time interval between taking the study drug and the comparison drug depends on the duration of circulation of the drug in the body and must be at least 6 half-lives (T 1/2) - Volunteers spend the time after the end of the first study period before the start of the second at home, but must adhere to this period of the established regime.
3.5.4. SELECTION OF BLOOD SAMPLES DURING STUDY
BIOEQUIVALENCE
The biomaterial in which drug concentrations should be determined in bioequivalence studies are plasma, serum or whole
blood. The sampling scheme, as in any pharmacokinetic study, is determined by the shape of the drug concentration-time curve. The more complex the shape, the more frequently samples should be taken. The sampling time should ensure that several points are obtained for each fragment of the pharmacokinetic curve - at least two for the phase of initial increase in concentration and at least five for the phase of its decrease. The total duration of observation of drug concentrations should be at least 4 times the half-life.
When collecting blood samples, the following conditions must be strictly observed:
> blood is taken from the ulnar vein through a special cubital catheter;
> the first portion of blood (initial, that is, before taking the drug) is taken in the morning on an empty stomach 5-10 minutes after installing the catheter in the cubital vein;
> the timing of subsequent sampling corresponds to the research program and depends on the pharmacokinetics of the drug being studied;
> blood samples are carefully labeled (subject code, sample number and drug name);
> the time interval between blood sampling and its processing should not exceed 5 minutes;
> plasma or serum samples should be stored at a temperature not exceeding -20 °C;
> the first meal is allowed no earlier than 4 hours after taking the drug;
> if unforeseen situations arise that exclude the possibility of blood sampling within the established time interval, work with this subject continues, but the encrypted tube remains empty.
3.5.5. METHODS FOR DETERMINING DRUG CONCENTRATIONS IN BLOOD SAMPLES WHEN STUDYING BIOEQUIVALENCE
To determine the concentration of drugs in plasma, serum or whole blood, various methods can be used (physicochemical, immunological, microbiological and others), providing the ability to confidently monitor the concentration of the drug under the selected conditions of the pharmacokinetic study, in particular its duration, and meeting the general requirements of selectivity, accuracy, reproducibility.
If, due to presystemic elimination of a drug, it is not detected in the blood in an unchanged state and (or) does not have biological activity (prodrug), it is necessary to determine the concentration of the biologically active metabolite, and not the prodrug.
3.5.6. PHARMACOKINETIC ANALYSIS
DATA. ASSESSMENT OF BIOEQUIVALENCE
Assessment of the bioavailability of a drug or its main biologically active metabolite (if the drugs studied are prodrugs) is based on a comparison of the values of pharmacokinetic parameters obtained from the analysis of “concentration C - time t” curves for the drug under study and the reference drug.
Individual values of the area under the concentration-time curves - AUC (both within the duration of observation of the concentration of the drug - AUQ, and within the range from 0 to °° - AUCL), the maximum concentration C max and the time to achieve it f max should be calculated according to the “concentration - time” data established for each subject for each of the studied drugs. The values of the parameters A11C g, C max and t max can be estimated both by model methods (by describing the “drug concentration - time” data with a mathematical model) and by non-model methods (the largest of the measured concentration values - C max and the corresponding time of the observed maximum - imax). The AUC* value is calculated using the ordinary or log trapezoidal method. AUCL values are determined by the formula: AUCL = AUC t + C t /K el where C t and K e1 are the calculated values of the drug concentration in the last sample and the elimination constant, respectively. To calculate C t and K e i, the final (monoexponential) section of the pharmacokinetic curve is described using nonlinear regression analysis or a straight line equation in In C - t coordinates using the linear regression method.
If the follow-up period is sufficient, when AUC t > > 80% AUCoo, AUC* values should be used to assess the complete absorption of the study drug, and provided that AUCj Subsequent analysis of pharmacokinetic data involves calculating individual ratios AUC t or AUC, (f and f, respectively - estimates of the relative degree of absorption) and C max (/") for any dosage forms, the ratios C max /AUC* or C max /AUCoo as characteristics of the absorption rate - for regular forms, and for long-acting forms - the differences between the values of C max and minimum concentration C min, related to the integral average concentration C ss = AUC t /t, where t is the duration of observation of the concentration of the drug substance.
Bioequivalence assessment is carried out according to the parameters AUCf or AUC^, as well as C max - for any dosage forms, according to the parameters C max /AUC f or C raax /AUCoo - for conventional forms and according to the parameter (C max - C min) / C ss - for long-acting forms.
Drugs are considered bioequivalent if the 90% confidence interval for the geometric mean, calculated for the individual ratios of the logarithmically transformed values of each of the listed pharmacokinetic parameters (with the exception of Cmax), for the study drug to those for the reference drug, is within 0.80. ..1.25. For C check the corresponding limits are 0.70...1.43. The limits of the above confidence interval are calculated using two one-sided tests (preferably Schuirmann's method) after logarithmic transformation of the pharmacokinetic parameter values.
If the named confidence interval in the case of AUC* or AUCoo parameters is outside the established limits, the drugs are considered non-bioequivalent
Often the term "Generic" is incorrectly replaced by the term "equivalent drug substance". Actually, such a term is meaningless, since there is no concept of “equivalence of medicinal substances”. The following types of equivalence are distinguished: pharmaceutical, biological and therapeutic. In the European Union and the United States, definitions of pharmaceutical equivalence of medicinal substances are used.
Medicines are pharmaceutically equivalent if they contain the same active substances in the same quantity and in the same dosage form and meet the requirements of the same or similar standards (EMEA, The rules governing medicinal products in the European Union Investigation of Bioavailability and Bioequivalence, v. 3C, 1998, pp. 231-244).
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 strength or concentration of active substances (FDA, Electronic Orange Book. Approved Drug Products with Therapeutic Equivalence Evaluations, 20th Edition, 2000).
The similarity of ingredients determines the pharmaceutical equivalence of drugs; to assess their biological equivalence, it is necessary to compare the characteristics of absorption and distribution of drugs in the human body. The World Health Organization proposes the following formulation: “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.”
Europe and the USA have adopted their own formulations of bioequivalence.
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 the extent that their efficacy and safety are substantially the same (EMEA, The rules governing medicinal products in the European Union. Investigation of Bioavailability and Bioequivalence, v.3C, 1998, pp. 231-244).
Bioequivalent drugs are pharmaceutically equivalent or pharmaceutically alternative drugs that have comparable bioavailability when studied under similar experimental conditions (FDA, Electronic Orange Book, Approved Drug Products with Therapeutic Equivalence Evaluations, 20th Edition, 2000).
Thus, assessing the equivalence of medicinal products comes down not only to assessing the identity of the molecules - the active principles of medicinal substances. The requirements for drugs when confirming their equivalence affect such aspects as production quality control (compliance with GMP standards), drug instructions, labeling, etc.
The equivalence of drugs is also assessed by the physicochemical properties of active substances (degree of dispersion, polymorphism, etc.), properties of excipients, features of the technological process, storage conditions, packaging (glass, plastic, paper, etc.).
1. Bioequivalence of a generic should be determined in relation to the original drug. If it is not represented on the national market, then it is taken from the list indicated (primary market), where, in the opinion of the manufacturing company, it best meets the requirements for quality, safety, effectiveness and labeling.
2. If it is impossible to use the original medicinal product, the leading medicinal product in the country’s market can serve as a standard, if its quality, safety and effectiveness are confirmed.
3. In the absence of a lead drug, the registered generic product is manufactured in accordance with local, state or regional standards, including the International Pharmacopoeia and the WHO Guide to Registration Requirements to determine the interchangeability of medicinal products produced by several manufacturers (WorldHealth Organization, 1996, WHO Expert Committee on Specifications for Pharmaceutical Preparations: thirty-fourth report. WHO Technical Report Series No. 863, Geneva, pp. 114-154).
The question naturally arises whether the described types of equivalence are sufficient to consider that generic drugs and original drugs are the same in therapeutic terms, that is, therapeutically equivalent.
According to European and American definitions, therapeutic equivalence provides, in addition to a similar pharmacokinetic profile, a similar assessment of the pharmacodynamic (therapeutic) effect.
A medicinal product is therapeutically equivalent to another medicinal product if it contains the same active substance or drug substance and, based on the results of clinical trials, has the same effectiveness and safety as the comparator drug, whose effectiveness and safety have been established (The rules governing medicinal products in the European Union, Investigation of Bioavailability and Bioequivalence, v. 3C, 1998, pp. 231-244).
Drugs can be considered therapeutically equivalent only if they are pharmaceutically equivalent and can be expected to have the same clinical effect and safety profile when used by patients according to their label directions (FDA, Electronic Orange Book. Approved Drug Products with Therapeutic Equivalence Evaluations, 20th Edition, 2000).
Unlike bioequivalence, the definition of which is regulated by strict standards and, as a rule, does not cause ambiguities in the interpretation of results, the lack of clear definitions of therapeutic equivalence leads to uncertainty for both doctors and patients in the correct choice of certain generic drugs.
The FDA's draft rules for assessing the therapeutic equivalence of generic drugs, published in 1998, propose that the drug label indicate the presence or absence of therapeutic equivalence, as well as the drug to which the comparison was made (usually the brand-name drug).
At the moment, when choosing a generic drug, one can be guided by the fact that the bioequivalence of medicinal substances is an indirect confirmation of their therapeutic effectiveness.
Full confidence in the similar effectiveness of drugs from the same generic line can only be achieved after comparative testing for therapeutic equivalence, data that will make it possible to fully take advantage of the economic advantages of the widespread use of generics. Currently, therapeutic equivalence testing is becoming mandatory when introducing new generic drugs to the market.
ACTUAL TOPIC
EQUIVALENCE OF GENERIC DRUGS: PHARMACEUTICAL ASPECTS
A. P. Arzamastsev, V. L. Dorofeev
Moscow Medical Academy named after. I. M. Sechenova
DISSOLUTION TEST
Pharmacokinetic tests are quite expensive and time-consuming. Therefore, in recent years, the issue of the applicability of the “dissolution” test, well known from pharmacopoeial analysis, to establish the bioequivalence of generics has been actively discussed.
Of course, there is a problem of correlation between the results of experiments conducted in vitro And in vivo, since such a correlation is not always possible to identify. Moreover, despite the obvious differences in release rates in vitro, significant differences in bioavailability may not be detected, and vice versa - the same dissolution test indicators do not always determine the bioequivalence of generics. However, it is known that in the case of therapeutic nonequivalence of drugs, there is often a difference in the rate of release of the active substance from the dosage form, which gives rise to the use of the “dissolution” test as an alternative to pharmacokinetic tests.
For solid oral dosage forms (tablets, dragees, capsules, granules), the dissolution test is one of the most important quality criteria. In fact, its use in drug analysis
ACTUAL TOPIC
of the drug and there is an attempt to introduce into the ND a test that, along with the assessment of pharmaceutical equivalence, would allow for at least an approximate assessment of bioequivalence.
It is known that two groups of factors influence the release of a drug from a drug.
1. Physico-chemical properties of substances
tions.
Solubility of the substance.
Particle size of the substance.
Crystalline state of the substance.
forms.
Manufacturing technology.
Excipients.
In accordance with these criteria, 4 groups of substances are distinguished:
They dissolve well and are well absorbed.
They dissolve poorly and are well absorbed.
They dissolve well and are poorly absorbed.
They dissolve poorly and are poorly absorbed.
Medicines of the 2nd group are classic objects for research using the “dissolution” test, since it is for them that the production technology is of greatest importance: the particle size of the substance, its crystalline state, the type and properties of the dosage form.
6 www. fda. gov.
At the same time, the question arises about the need to use the “dissolution” test for substances of the 1st and 3rd groups. The properties of the dosage form, particle size and crystalline state of the substance in this case do not significantly affect the release of the active substance. Moreover, in group 1 there are no “bottlenecks” at all. However, the FDA in this case indicates that the test is worth conducting, and if the active substance is released in 15 minutes by at least 85%, then we can say that dissolution does not affect bioavailability, since the determining factor in this case will be the rate of gastric emptying.
Regarding the correlation of tests in vivo And in vitro The FDA indicates that such a correlation is more likely to be found for group 2 and less likely to be found for groups 1 and 3.
Next, the following question arises: are the dissolution tests carried out within the framework of the ND sufficient to allow a conclusion about bioequivalence to be made based on their results? The evaluation of drugs by the “dissolution” test in pharmacopoeial analysis is carried out at one time point. Usually this is 45 minutes, unless otherwise specifically stated in the ND for a specific drug. A number of authors have shown that single-point analysis is insufficient for generic comparisons. Such an analysis gives an approximate idea only of the degree of release of the active substance. Moreover, each manufacturer, in accordance with general pharmacopoeial requirements, is free to independently choose the dissolution medium and rotation speed of the stirrer or basket. And if he fails to produce a high-quality generic (bioequivalent to the original drug), then he can simply increase the stirring speed to achieve the notorious 70% dissolution in 45 minutes.
Therefore, when using the dissolution test to assess bioequivalence, several time points should be obtained from which the release curve is constructed, and the test drug and the reference drug should be tested under the same conditions. WHO recommendations indicate that in some cases, comparison of the dissolution profiles of the test and original drugs can serve as the basis for a conclusion about their bioequivalence.
Another question: when can one limit oneself to establish bioequivalence?
VEDOMOSTI NC ESMP, 1, 2007
"dissolution" test? WHO recommends focusing, firstly, on the dissolution rate: pharmacokinetic studies can be omitted if the drug is released very quickly (at least 85% in 15 minutes) or quickly (at least 85% in 30 minutes) from the dosage form. Secondly, the similarity of the release profiles of the test and original drugs must also be proven (except for the case of “at least 85% in 15 minutes” - see below).
In pharmacokinetic studies, the curve must contain at least 2 points for the phase of increasing concentration and at least 5 for the phase of decreasing concentration. On the dissolution curve, the concentration only increases, so the number of points should be chosen depending on what drug is being analyzed and what drug it contains. For Group 1 and 3 drugs, the FDA recommends sampling every 5 to 10 minutes. This means that when analyzing drugs with unmodified release within 60-70 minutes, there must be at least 6 points on the dissolution curve. To compare the two dissolution profiles, an analysis of 12 units of the test product and 12 units of the original drug is required.
To compare release profiles, the FDA recommends using, inter alia, a model-independent method by calculating two parameters: the dissimilarity factor (/,) and the similarity factor (f 2 ) .
The difference factor shows the difference between the curves as a percentage and is calculated using the following formula:
I IVC
X 100,
A= L
Z*r
Where: P - number of time points, R t - release from the reference drug at the point t, %;
T t - release from the test drug at the point t, %.
The similarity factor evaluates, respectively, the similarity of two curves as a percentage and is calculated using the formula:
/, = 50 x l g
t = 1
It is considered that there is no difference between the curves if:
the difference factor takes values from 0 to 15;
The similarity factor takes values from 50 to 100.
the number of time points taken into account must be at least 3;
the test conditions for both drugs should be the same and sampling should be carried out at the same time intervals;
after reaching the release level of 85% of both drugs, all points up to this level and one subsequent point can be taken into account;
the coefficient of variation for the first time point should be no more than 20% and for subsequent ones no more than 10%.
Features of patent protection of original drugs
Indeed, the company that developed the original drug can be understood. Enormous funds that are spent on searching for a molecule of a drug substance, researching a drug, bringing it to market, carefully monitoring possible adverse effects and interactions, after a few years, when patent protection continues to apply, turn out to be seemingly irretrievably lost.
A generic drug, which is often produced by several companies at the same time, “inherits” all the properties, effort, time and money that the original drug does. And you can argue as much as you like that the original always remains the original, and the reproduced medium is just a reproduced medium. The common international nonproprietary name makes these drugs similar for the consumer, and the generic, due to its usually lower price, is more attractive.
Manufacturers of original pharmaceutical brands protect their exclusive rights in various ways, primarily through patent law. The implementation of patent protection for a particular molecule underlying a medicinal substance provides for a ban on its reproduction for a period, the duration of which varies in different countries, but on average it
Generics and copies
A generic drug is a drug for which patent protection has already expired. Accordingly, a generic drug is not the exclusive property of the pharmaceutical company that developed it or held the first license to sell it.
Copies- these are medicines that are presented on the markets of countries with weak or absent patent protection of chemical molecules - the active ingredients of medicines.
In essence, the difference between a copied drug and a generic drug is only a violation of the legal rules for the reproduction of a medicinal product (infringement of the rights of the patent holder).
Ultimately, in countries with developed patent protection, consumers are faced with the original drug, and only then generic drugs have to gain their place in the market.
Secondly, the traditions of Soviet medicine and the long-term presence on the market of exclusively domestic drugs or drugs produced in the former CMEA countries provoked some shift in the perception of brand names. Thus, Piracetam for Russian doctors is primarily a generic drug Nootropil; Co-trimoxazole is better known as Biseptol; Renitek (enalapril maleate) came into use under the name of its most successful generic on the Russian market - Enapa; the original ciprofloxacin (Tsiprobay) is replaced by the names Tsifran and Tsiprolet.
Thus, the specifics of the market dictate the perception of original names, which determines the subjective choice between the original and the generic in favor of the latter.
Thirdly, like any country with a high level of government protectionism in the field of medicine, Russia chooses generic drugs because they are expensive. This determines the filling of the most widespread sector of medicine with generics - free medicine.
The active anti-generic policy pursued by the developers of original drugs has led to the fact that the term generic itself has acquired a certain offensiveness. This contributes to the fact that the implicit characteristics of a generic drug are its inferiority, insufficient study, and unspecified safety profile. Meanwhile, there are no objective grounds for this.
When evaluating generic drugs, keep the following in mind.
- The generic contains the same active medicinal substance (substance) as the original (patented) drug.
- The generic differs from the original drug in excipients (inactive ingredients, fillers, preservatives, dyes, etc.).
- Differences are also observed in the technological process of producing generics.
Often the term "generic" is incorrectly replaced by the term "equivalent drug substance". Actually, such a term is meaningless, since there is no concept of “equivalence of medicinal substances”. The following types of equivalence are distinguished: pharmaceutical, biological and therapeutic. In the European Union and the United States, definitions of pharmaceutical equivalence of medicinal substances are used.
It was noted above that the therapeutic effectiveness (bioavailability) and safety of a drug can be significantly influenced by a number of exogenous (pharmaceutical) factors. According to modern biopharmaceutical concepts, a drug affects the pathological process in the body with its entire set of properties , and not just a medicinal substance. This means that medications containing the same pharmacological substance in the same dose and in the same dosage form, but from different manufacturers, may not be equivalent (from the Latin aequivalens - equivalent, equivalent). Indeed, 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 prescription. application. To understand the seriousness of the problem, I recommend referring to the report by C.N. Nightingale at the 5th Conference on Macrolide Antibiotics to study the equivalence of the original drug clarithromycin with 40 copies produced in 13 countries in Latin America, Asia and Africa (Nightingale CH. A survey of the Quility of Generic Clarithromydn Product from 13 Countries. Clin Drug Invest 2000 ;19:293-05.).
It should be noted that the problem of drug equivalence is closely related to the emergence of generic drugs - the so-called “generic forms” or “generics”). An analysis of the pharmaceutical market in many countries shows that a significant part of the turnover of drugs is not original products, but their cheaper copies or analogues. For example, in the USA, generics account for more than 12% of drug sales; in Western European countries this figure ranges from 30 to 60%. A generic (reproduced drug) is a copy of the original drug, which pharmaceutical companies have the right to produce and put on the market after the patent protection period for the original drug expires.
In order to understand the essence of this serious problem, it is necessary to define such concepts as “original medicine” and “reproduced medicine” (generic) with official formulations.
According to the recommendations of the World Health Organization (WHO): “An original (innovative) drug is a drug that has been registered for the first time based on complete documentation regarding its quality, safety and effectiveness, protected by patent for up to 20 years" Generic medicines have a number of equivalent commonly used synonyms - “generics”, “generics”, “generic medicines”. A generic medicinal product is considered to be a medicinal product that has the same qualitative and quantitative composition of active substances and the same dosage form as the reference drug, and whose bioequivalence to the reference drug is confirmed by appropriate bioavailability studies.” 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.
At the same time, WHO recommends using the term “multisource drugs” as a basic concept – a drug produced by several companies.
In the Federal Law “On the Circulation of Medicines” No. 61-FZ of 2010, these concepts are fully disclosed and taking into account international recommendations:
« Original medicine - a medicinal product containing a pharmaceutical substance obtained for the first time or a new combination of pharmaceutical substances, the effectiveness and safety of which are confirmed by the results of preclinical studies of drugs and clinical studies of drugs.”
"Reproduced medicine- a medicinal product containing the same pharmaceutical substance or a combination of the same pharmaceutical substances in the same dosage form as the original medicinal product, and put into circulation after the original medicinal product went into circulation.”
It is obvious that the mass production of generics has, first of all, purely economic reasons:
☻ There is no need to create and maintain advanced scientific infrastructure and invest huge amounts of money in the search for original “hits” and their expensive (according to GLP requirements) preclinical study;
☻ No need to buy a production license from the creator’s company - the patent has expired;
☻ Large-scale and very expensive clinical studies (according to GCP requirements) are not required to register a generic product. After all, a generic is a drug that is registered on the basis of an incomplete dossier (a set of registration documents) - only confirmation of its equivalence to the original drug is required.
The reproduced drug must meet a number of requirements:
Have similar bioavailability;
Available 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.
Despite the widespread use of the concept of equivalence, “generic equivalence” as a term is meaningless. WHO recommends using the term “interchangeability” for generic drugs. An interchangeable generic drug is a therapeutically equivalent generic drug that can replace a comparator drug in clinical practice.
The following features of generic drugs must be taken into account:
The generic contains the same active medicinal substance (substance) as the original (patented) drug;
The generic differs from the original drug in excipients (inactive ingredients, fillers, preservatives, dyes, etc.);
Differences are also observed in the technological process of producing generics.
According to international standards, the conformity of a generic and an original drug (brand) is based on three important components: pharmaceutical, pharmacokinetic and therapeutic equivalence.
Pharmaceutical equivalence- complete reproduction by a generic drug of the composition and dosage form of the original drug. In the European Union, medicinal products are considered pharmaceutically equivalent if they contain the same active substances in the same quantity and in the same dosage form and meet the same or similar standards.
In the United States, the FDA requires pharmaceutically equivalent drugs to contain the same active ingredients in the same dosage form, be intended for the same route of administration, and be identical in strength or concentration of the active substances.
Bioequivalence (pharmacokinetic equivalence)- similarity of pharmacokinetic parameters of the original and generic drugs. The World Health Organization proposes the following formulation of bioequivalence: “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.” In the European Union, two medicinal products are considered 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. In the United States, bioequivalent drugs are pharmaceutically equivalent or pharmaceutically alternative drugs that have comparable bioavailability when studied under similar experimental conditions. In the Russian Federation, two drugs are bioequivalent if they provide the same bioavailability of the drug.
Therapeutic equivalence- efficacy and safety similar to the original drug for the generic drug in pharmacotherapy. According to European and American standards, therapeutic equivalence provides, in addition to a similar pharmacokinetic profile, a similar assessment of the therapeutic effect. According to EU rules, a medicinal product is therapeutically equivalent to another medicinal product if it contains the same active substance or medicinal substance and, according to the results of clinical studies, it has the same effectiveness and safety, as well as a comparator whose efficacy and safety have been established. In the United States, drugs can be considered therapeutically equivalent only if they are pharmaceutically equivalent and can be expected to have the same clinical effect and the same safety profile when used by patients as directed on the label.
Based on the above formulations, it is clear that in developed countries they have long come to understand the fact that pharmaceutical and pharmacokinetic equivalence is not enough to consider that generic drugs and original drugs are the same in therapeutic terms, that is, therapeutically equivalent and that bioequivalence is not a guarantee, but only an assumption of therapeutic equivalence and safety of the drug.
In the Russian Federation, the situation with generic drugs is somewhat different:
Russia has the highest share of generics on the pharmaceutical market - according to various sources, up to 95% of the drug market!!!;
Many generics appeared in Russia before their originals!!!;
There is usually no data on the therapeutic equivalence of generics and brand!!!;
If a generic product is approved for use in other countries, it is registered in the Russian Federation according to a simplified scheme (without determining bioequivalence). Only generics from new manufacturers are tested for bioequivalence. For example, from 1256 of foreign drugs registered in 2001 only 22 passed the bioequivalence examination upon registration in the Russian Federation!!!;
We have the most expensive generics in the world.
Obviously, this is primarily due to the existing regulatory framework regarding generic medicines.
According to the standards of the Russian Federation, assessment of bioequivalence (“pharmacokinetic equivalence”) of medicines is the main type of medical and biological control of reproduced (generic) medicines that do not differ in dosage form and content of active substances from the corresponding original medicines. It is believed that Bioequivalence studies allow one to make informed conclusions about the quality of the drugs being compared using a relatively smaller amount of primary information and in a shorter period of time than during clinical trials. At the same time, bioequivalence studies (pharmacokinetic equivalence) are not considered as an alternative to pharmaceutical equivalence tests - the equivalence of generic medicinal products in terms of qualitative and quantitative composition, assessed by pharmacopoeial tests, since pharmaceutical equivalence does not guarantee pharmacokinetic equivalence. At the same time, Bioequivalence studies suggest that generic drugs that are pharmacokinetically equivalent (bioequivalent) to the original provide the same effectiveness and safety of pharmacotherapy, i.e. that they are therapeutic equivalents.
In this regard, in relation to generic medicines, in accordance with Article 26 of the Federal Law of the Russian Federation of April 12, 2010 N 61-FZ “On the Circulation of Medicines”, the so-called accelerated procedure for registration of medicines is applied:
Article 26. Accelerated procedure for the examination of medicines
1. The accelerated procedure for the examination of medicines for the purpose of state registration of medicines is applied to generic medicines. When carrying out such a procedure, information obtained during clinical trials of medicinal products and published in specialized printed publications is presented, as well as documents containing the results of a study of bioequivalence and (or) therapeutic equivalence of a medicinal product for medical use or the results of a study of bioequivalence of a medicinal product for veterinary use.
The procedure and all stages of conducting bioequivalence studies are regulated in detail by the Methodological Instructions of the Ministry of Health and Social Development of the Russian Federation dated August 10, 2004 “Conducting high-quality studies of bioequivalence of medicines.” The objects of bioequivalence studies are generic medicinal products intended for oral administration, cutaneous application, or rectal administration, provided that their effect is mediated by the appearance of the active substance in the systemic circulation. Bioequivalence assessment is carried out for all long-acting dosage forms; forms that provide immediate release of the drug when taken orally (tablets, capsules, suspensions, etc., with the exception of solutions); transdermal therapeutic systems; rectal and vaginal suppositories, as well as combination medications (by main components). Bioequivalence studies are not conducted for medicinal products intended for administration by inhalation.
The corresponding original medicinal product registered in the Russian Federation is used as a reference drug.
The assessment of the bioequivalence of all drugs, with the exception of psychotropic drugs and drugs used for HIV infection, is carried out on healthy volunteers. Individuals of both sexes aged 18 to 45 years who meet a number of criteria, including the absence of chronic diseases, allergy history, drug intolerance, prior use of medications, etc., can be recruited as healthy volunteers. Participation of healthy subjects and patients in bioequivalence studies of drugs is voluntary. A volunteer has the right to refuse to participate in ongoing research at any stage. Ethical standards for conducting bioequivalence tests are regulated by relevant documents. Volunteers included in the bioequivalence study sign written informed consent. The volunteer is provided with all necessary information about the study drug and the study procedure. The volunteer is guaranteed that, if necessary, he will be provided with qualified medical care both during and after the bioequivalence study, and that information about him obtained during the research will be confidential. After signing the informed consent, a clinical and paraclinical examination of volunteers is carried out, as well as laboratory tests (clinical blood test (clinical urine test, biochemical blood test, blood test for HIV, syphilis, viral hepatitis). Bioequivalence studies are carried out with one dose of the reproduced medicinal product in a given dosage form, even if it is declared for registration in several dosages.When conducting bioequivalence studies, the concentration of active substances is determined in plasma, serum or whole blood.
To determine the concentration of active substances in plasma, serum or whole blood, various methods can be used (physicochemical, immunological, microbiological, etc.), providing the possibility of obtaining reliable laboratory data on the concentration of the active substance under the selected conditions of a pharmacokinetic study, in particular its duration, and meeting the general requirements of selectivity, accuracy, and reproducibility.
If, due to presystemic elimination of the drug, it is not detected in the blood in an unchanged state and does not have pharmacological activity (prodrug), it is necessary to determine the concentration of the biologically active metabolite.
The bioequivalence of the reference drug and the generic drug is assessed by the degree and rate of absorption of the drug, the time to reach the maximum concentration in the blood and its value, the rate of elimination of the drug (AUC - area under the “concentration of the active substance - time” curve; Cmax - maximum concentration of the active substance; tmax - time to reach the maximum concentration of the active substance; T1/2 – half-life of the drug, etc.).
These are the approaches to assessing and interpreting the bioequivalence of medicines that are in effect on the territory of the Russian Federation.
I would like to draw your attention to the following features of solving the problem of generics in developed countries:
1. The presence of a developed and effectively functioning drug quality control system, which is based on strict adherence to the principles of evidence-based medicine and standards GLP, GMP, GCP, GDP, GPP, GSP - from the development stage to its receipt by the consumer;
2. Bioequivalence is not considered a guarantee of therapeutic equivalence between the generic and brand. Generics undergo clinical trials according to GCP rules.
3. In the USA, generics that have undergone clinical trials for therapeutic equivalence and have differences in bioequivalence of no more than 3-4% are assigned a code "A". Generics with code "A" may be a replacement for the original drug for financial reasons.
4. In the USA, generics that have not undergone clinical trials for therapeutic equivalence are assigned a code "IN". Generic with code "IN" cannot be an automatic replacement for the original drug or another generic with the code "A".
5. In a pharmacy, a pharmacist can dispense a drug to a patient only with the trade name prescribed by the doctor.
6. Information on the status of drugs is publicly available and contained in the “Orange Book” reference book (FDA, Electronic Orange Book.Approved Drug Products with Therapeutic Equivalence Evaluations)
According to a number of Russian experts:
All generic drugs must undergo therapeutic equivalence studies.
- The use of a generic is possible if the drug is registered in a country with a developed drug quality control system and the manufacturing company has proven therapeutic equivalence in post-registration clinical studies;
It is necessary to have complete information on compliance with GMP requirements in the production of generics
It is necessary to create a database accessible to the medical community on the pharmacokinetic and therapeutic equivalence of generics similar to the Orange Book.
