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.
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.
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 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.
Issues of interchangeability of drugs are the most controversial and complex issues in the pharmaceutical market. The relationship between original and generic drugs (or generics) is far from cloudless.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.
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.
It should be noted that currently there are different methods for determining the bioequivalence of drugs, developed by the Pharmacological Committee of the Ministry of Health of the Russian Federation91, the US FDA92, the World Health Organization, the European Agency for the Evaluation of Medicines93, as well as other international and national documents.
According to the requirements of the Pharmacological Committee of the Russian Ministry of Health, “two drugs are bioequivalent if they provide the same bioavailability of the drug.” Similar requirements are given by the Scandinavian Medical Council94. Obviously such
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
|
Class drugs |
Solubility |
Permeability |
Correlation of in vitro and in vivo parameters |
|
I |
High |
High |
Exists if the dissolution rate is lower than the gastric exit rate, otherwise there is little or no correlation |
|
II |
Low |
High |
Exists if in vitro and in vivo dissolution rates are the same, provided the dose is not too high |
|
III |
High |
Low |
Correlation is determined by absorption (permeability), little or no correlation with solubility |
|
IV |
Low |
Low |
Weak or no correlation |
|
Table 1.23. Recommended markers for classifying the permeability of active components of generic drugs |
||
|
Marker |
Permeability |
Notes |
|
a-methyldopa |
Low |
Amino acid transporter |
|
Antipyrine |
High |
Permeability marker |
|
Atenolol |
Low |
Intercellular permeability standard |
|
Verapamil |
High |
- |
|
Hypothiazide |
Low |
Class IV (Table 1.22) |
|
Carbamazepine |
High |
- |
|
Ketoprofen |
High |
- |
|
Caffeine |
High |
- |
|
Mannitol |
High |
Permeability boundary marker |
|
Metoprolol |
High |
Internal standard low to high permeability |
|
Naproxen |
High |
- |
|
Polyethylene glycol |
Low (molecular weight 4000) to high (molecular weight 400) |
Can be used as a non-absorbable marker |
|
|
||
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:
- values of areas under pharmacokinetic curves;
- their relationship;
- 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.
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