Pharmaceutical Equivalence

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

The 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 (for pH adjustment)

water for injections

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

Bioequivalence

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

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

If a generic 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 is costly for patients, because. generics may not match the original drug in terms of their pharmacokinetic properties. On the example of a control check of the bioequivalence of generics to the original clarithromycin, C.N. Nightingale et al compared the original 40-copy clarithromycin product for bioequivalence using USP 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 terms of the amount of active principle in one unit of the product. The amount of impurities that are not related to the active principle in most samples is greater than in the original. In the "best" generic they were 2%, in the "worst" - 32%. The presence of impurities determined the severity of adverse reactions.

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

1. The interchangeability of medicinal products for medical use is determined in the manner established by the Government Russian Federation, based on the following parameters:

1) equivalence (for biosimilar (biosimilar) medicinal products (biosimilars) - comparability) of qualitative and quantitative characteristics of pharmaceutical substances (the use of various salts, esters, complexes, isomers, crystalline forms and other derivatives of the same active substance is not an obstacle to interchangeability medicinal products, if during the study of the bioequivalence of the medicinal product or if it is impossible to conduct this study during the study of the therapeutic equivalence of the medicinal product, the absence of clinically significant differences in the pharmacokinetics and (or) safety and efficacy of the medicinal product for medical use is proved);

2) equivalence dosage form(Equivalent dosage forms are understood to mean different dosage forms that have the same route of administration and method of administration, have comparable pharmacokinetic characteristics and pharmacological action and also ensuring the achievement of the desired clinical effect. Differences in dosage forms are not an obstacle to their interchangeability, if during the study of the bioequivalence of the medicinal product or if it is impossible to conduct this study during the study of the therapeutic equivalence of the medicinal product, the absence of clinically significant differences in the pharmacokinetics and (or) safety and efficacy of the medicinal product for medical use) ;

3) equivalence or comparability of the composition of the excipients of the medicinal product for medical use (differences in the composition of the excipients of the medicinal product for medical use are not an obstacle to their interchangeability, if during the bioequivalence study of the medicinal product for medical use or if it is impossible to conduct this study during the study therapeutic equivalence of the medicinal product for medical use, the absence of clinically significant differences in the pharmacokinetics and (or) safety and efficacy of the medicinal product for medical use has been proven. adverse reactions in certain groups of patients or an increase in the frequency of their occurrence);

4) the identity of the method of administration and use;

5) the absence of clinically significant differences during the study of the bioequivalence of the medicinal product or, if it is impossible to conduct this study, the absence of clinically significant differences in the safety and efficacy of the medicinal product during the study of therapeutic equivalence. This parameter does not apply to generic drugs specified in Part 10 of Article 18 of this Federal Law. With regard to biosimilar (biosimilar) medicinal products (biosimilars), data on the absence of clinically significant differences in the safety, efficacy and immunogenicity of the medicinal product based on the results of the clinical research are provided in the manner prescribed by this part;

6) compliance of the manufacturer of the medicinal product with the requirements of good manufacturing practice.

2. Comparison of the parameters of registered medicinal products for medical use is carried out by a commission of experts of an expert institution during the examination of such medicinal products in the process of their state registration. The conclusions of experts on the interchangeability or non-interchangeability of medicinal products for medical use, made as a result of this comparison, are drawn up in the form of an annex to the expert opinion in the form approved by the authorized federal executive body.

3. The provisions of this article do not apply to reference medicinal products, herbal medicinal products, homeopathic medicinal products and medicinal products that have been approved for medical use in the Russian Federation for more than twenty years and for which it is impossible to conduct a bioequivalence study.

The problem of interchangeability medicines (LS) is currently being discussed quite actively at various levels both in our country and abroad. It has both a purely therapeutic and rather relevant economic background. It should be noted that in our country there is still no clear definition of interchangeable drugs. The interpretation of this concept very much depends on the opinions of various specialists and their experience in using drugs. A completely different attitude to this term may arise when solving purely therapeutic problems and problems related to the purchase of drugs under government contracts.

However, we will focus on some specific aspects of the interchangeability problem. From a therapeutic point of view, it is obvious that two different drugs (that is, containing two different active substances) of the same pharmacological group can replace each other, provided that they have, for example, the same mechanism of action (say, blockade of the same receptors) and that, if necessary, appropriate adjustments to doses and frequency of administration will be made. And in this sense, these two drugs for the doctor will be interchangeable: now one is not on sale, and he will prescribe another. This is the so-called therapeutic substitution, but it is not identical with the concept of interchangeability. Currently, this term refers to the replacement of the original drug with a generic drug or the replacement of one generic drug with another with the same active substance. In this, at least, there is already a certain agreement. But what original drugs and generics should be considered interchangeable and what problems stand in the way of resolving this issue, we will discuss in this article.

The problem of the equivalence of reproduced drugs (generics) is quite acute due to a large number drugs from various manufacturers on the market. This issue is relevant throughout the world, but in our country over the past two decades it has acquired particular significance, since we were not ready for a huge flow of drugs. Our regulatory system, the scientific basis and all concepts have been adapted for a market suffering from a shortage of drugs. Now the situation has changed dramatically. The Russian pharmaceutical market is saturated with a large number of drugs. For some active substances (paracetamol, acetylsalicylic acid, sodium diclofenac, metamizole sodium, enalapril maleate, ciprofloxacin hydrochloride, etc.), several hundred drugs from different manufacturers were registered 10 years ago (taking into account different dosage forms and dosages). Now the number of corresponding drugs has slightly decreased, but this in no way removes the problem of generics.

What is the question? After all, an excess of goods should contribute to competition, the struggle for the client by improving the quality of products and reducing their cost. And it is from this place that in the future in this article we will try to avoid the word “product”, since we will talk about drugs, i.e. about products with unique properties, for which the primary criteria are quality, efficiency and safety. Everything else is a consequence - both the price of drugs, and the health that we risk losing when using drugs that do not meet modern requirements.

Requirements for drugs

Starting the discussion of approaches to assessing the interchangeability of drugs, it is worth citing an excerpt from the joint statement of the International Federation of Pharmaceutical Federations (FIP, www.fip.org) and the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA, www.ifpma.org), adopted in 1999, in which, in particular, states that the replacement of the original drug with a generic one “should be carried out only if there is compliance with accepted international standards, including bioequivalence, in order to guarantee the quality of all drugs on the market” .

The same document states: “All governments should take steps to ensure the quality, safety and efficacy of all drugs available in their respective countries, in accordance with accepted international standards. This applies to both original and generic drugs, to the private and public sectors, and to imported and locally produced products.”

Thus, there are three requirements for any drug: efficiency, safety and quality. This approach to the evaluation of drugs is currently accepted all over the world, incl. and in our country.

The categories "efficacy" and "safety" refer to biomedical issues, while "quality" is a purely pharmaceutical problem and reflects the compliance of drugs with the requirements of regulatory documentation in terms of authenticity (i.e., the identity of the contents of the package), purity (by the content of impurities) and the quantitative content of the active substance (or substances in the case of a combined preparation). The rules of Good Manufacturing Practice (GMP) are inextricably linked with the quality assurance and control of drugs.

Original and reproduced drugs. Basic terms

When discussing the issues of interchangeability of drugs, it is necessary to define the main terms. The Federal Law No. 61-FZ “On the Circulation of Medicines” provides the following definition: an original drug is a drug 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 trials of drugs. In foreign literature, you can find the corresponding terms "innovator product", "branded product". In WHO documents, an "innovator pharmaceutical product" is a product approved for use for the first time based on documentation of its quality, safety and efficacy.
The organization that developed the original drug receives patent protection for it for a long period (up to 20 years or more), which allows compensating high costs for the development of the tool and its promotion on the market, as well as to receive additional income. Original drugs have a high cost during patent protection and a higher cost compared to generics after it ends.

This circumstance causes constant criticism. It is argued that the costs declared by the leading manufacturers for the development of a new drug (i.e., a new molecule) are clearly overstated, as well as the cost of original products after the expiration of the patent.

But do not forget that, firstly, modern drugs have more subtle, targeted, selective mechanisms of action than drugs, for example, from the same pharmacological groups but developed several decades ago. Therefore, even with modern screening of active substances, which in some cases can significantly reduce the search time for a new active molecule, the search period, multiplied by the cost of modern high technologies used, turns into significant financial costs.

Secondly, we will not tire of repeating that the main driving force behind the development of the pharmaceutical industry are manufacturers of innovative drugs. It should be remembered that the profits received from the sale of original drugs are ultimately directed to the development of innovative drugs.

Generic drug - a drug containing the same pharmaceutical substance or a combination of the same pharmaceutical substances in the same dosage form as the original drug, and put into circulation after the original drug was put into circulation. In relation to reproduced drugs, the term "generic" or "generic" (generic product) is also used.

It should be noted that in WHO documents (www.who.int) due to the different interpretation of the term "generics" in different countries, it is recommended to use the term "multisource pharmaceutical products". The WHO defines them as pharmaceutically equivalent or pharmaceutically alternative drugs that may or may not be therapeutically equivalent. The term “multisource”, although not very euphonious and not coexisting in domestic terminology, but concretizes the understanding that reproduced drugs are produced from pharmaceutical substances and excipients of very different origins. That is, they are assembled as a designer - from parts from different manufacturers. Since, theoretically, suppliers can easily change, this is already a reason for criticism from the manufacturers of original drugs. Indeed, such an approach generally makes it difficult to ensure uniform quality, as well as compliance with efficiency and safety requirements.

In this regard, the definition of generic is interesting, which is given in Directive 2001/83 / EC of the European Parliament, which determines the requirements for medicines: generic medicinal product(generic medicinal product) means a medicinal product that has the same qualitative and quantitative composition in relation to the active substance and the same dosage form as the reference drug, and whose bioequivalence has been proven by bioavailability studies with respect to the reference drug. That is, the EU countries theoretically do not allow the presence on the market of generics with bioequivalence problems, although, of course, this does not exclude the corresponding problem at all.

According to the WHO definition, medicinal products are pharmaceutically equivalent if they contain the same amount of the same active substance (substances) in the same dosage form, meet comparable quality standards and are intended for the same route of administration. A similar, but more specific and practical definition is given by the US FDA (www.fda.gov): drugs are considered pharmaceutically equivalent if they contain (1) the same active ingredients (2) with the same dosage or concentration (3) in the same drug form, (4) are intended for a single route of administration, and (5) meet pharmacopoeial or other applicable standards for quantitative content, purity and identity.

WHO indicates that medicinal products are pharmaceutical alternatives if they contain the same amount of the same active principle, but differ in dosage form (for example, tablets and capsules) and/or in chemical form (different salts, esters). Pharmaceutical alternatives are designed for a single route of administration. In the definition of pharmaceutical alternative drugs, the FDA has approximately the same approach.

It should be noted that up to the present time in the literature, on the Internet, in oral speech, one can find rather loose use of the terms “drug synonyms”, “drug analogues”, “drug substitutes”, etc. We want to warn specialists against using this terminology without a clear indication of the context corresponding to the above approaches.

For example, the term "drug synonyms" continues to be incorrectly used in relation to generics. This would be at least somewhat justified if there were no problem of therapeutic equivalence, interchangeability. Therefore, different trade names of drugs cannot be synonyms. But for substances it can be, for example: metamizole sodium as an international generic name(INN) and analgin as the domestic pharmacopoeial name, paracetamol as the INN and acetaminophen as the US name (USAN).

Bioequivalence of generics

The same active ingredient, dosage, dosage form and route of administration bring together drugs from different manufacturers, but this does not mean that the effectiveness of generics will also be equivalent, because Differences in the quality parameters of the active substance (for example, polymorphism), in the composition of excipients and / or in the manufacturing process may lead to differences in the effectiveness of these drugs. This fact has long been known and has been discussed since the middle of the last century.

As a small digression, we note that the issue of the influence of impurities on the effectiveness and safety of generics is often discussed. On this occasion, it can be said that if the purity standards laid down in the unified state pharmacopoeial quality standard for drugs are observed, the issue of the influence of impurities is generally removed. Another thing is when such a quality standard (i.e., the State Pharmacopoeia) does not actually exist in its full form, and the existing regulatory documentation of manufacturers (FSP and ND) is very diverse. In this case, the question of impurities, as well as other quality parameters, remains open, which has an indirect effect on the efficacy and safety of drugs.

So, in connection with the heterogeneity of generics, the concept of biological equivalence arose. According to WHO documents, two medicinal products are bioequivalent if they are pharmaceutically equivalent or pharmaceutically alternative, and their bioavailability in terms of maximum plasma concentration (CMAX), time to reach this concentration (TMAX) and area under the pharmacokinetic curve (AUC) after applications at the same molar dose under the same conditions are similar to the extent that their effects are essentially the same. Approximately the same approach is taken by the European Medicines Agency (EMA, www.ema.europa.eu) and the FDA.

WHO and FDA recommend that bioequivalence be determined using the following in vivo and in vitro tests:
- comparative pharmacokinetic tests in humans (study of the concentration profile of the drug or its metabolites in biological fluids);
- comparative pharmacodynamic trials in humans (study of the effects caused by drugs);
— comparative clinical trials;
- Comparative studies in vitro (for example, the "dissolution" test).

The word "comparative" means that all of the above studies are carried out by comparing the relevant parameters in the test product and the comparator drug.

WHO publishes guidelines for choosing a comparator for essential drugs. These recommendations include, in particular, for each INN the brand name of the originator drug, which is recommended to be used as a comparator when establishing the interchangeability of generics. It also provides the appropriate dosage forms and dosages.

In the USA, the choice of a comparator drug is based on data presented in the so-called Orange Book, which we will discuss below. It also gives an indication of a specific drug in a specific dosage form, a specific dosage and a specific manufacturer. Drugs that can be used to compare generics with them are marked in the appropriate column. There is also domestic documentation, which provides instructions for conducting pharmacokinetic studies and the "dissolution" test to assess the bioequivalence of drugs.

Therapeutic equivalence and interchangeability

Finally, the most important concept is therapeutic equivalence. Important, because it is closest to understanding which drugs can be interchanged. Indeed, according to the WHO definition, an interchangeable drug is a drug that is therapeutically equivalent when compared with a comparator drug and for which the comparator drug can be replaced in clinical practice. The same position is reflected in the FDA documents.

We will also adopt an approach where therapeutically equivalent drugs are interchangeable. It remains only to resolve the question: which drugs are considered therapeutically equivalent?

Criteria for therapeutic equivalence

Let's start with the WHO definition: "two medicinal products are therapeutically equivalent if they are pharmaceutically equivalent or pharmaceutically alternative and, after their use in the same molar dose, their efficacy and safety are essentially the same when they are used in the same way under the conditions described in the instructions" .

Now here is the definition of therapeutic equivalence given by the FDA: "drugs are considered therapeutically equivalent only if they are pharmaceutically equivalent and have the same clinical effects and safety profile, and when they are used under the conditions described in the instructions" . That is, unlike the WHO, the FDA considers only pharmaceutically equivalent drugs as therapeutic equivalents. Thus, from the point of view of the FDA, capsules and tablets, for example, even in the same dose, will not be therapeutically equivalent. Moreover, the FDA, after a general definition, quite specifically describes all the conditions for therapeutic equivalence.

1. Medicines must be approved for use as effective and safe.
2. Preparations must be pharmaceutically equivalent.
3. Preparations must be bioequivalent, i.e. conditions must be met:
— they have no known or potential bioequivalence problems and meet the requirements of the relevant standard when tested in vitro, or
— they are known to have or may have potential bioequivalence problems, but have been shown to meet the requirements of an appropriate bioequivalence standard.
4. Preparations must have proper instructions.
5. Products must be manufactured in accordance with the requirements of Good Manufacturing Practice (ie GMP).

The FDA issues an important document officially titled "Approved Drug Products with Therapeutic Equivalence Evaluations", which can be roughly translated as "Approved Drug Products with Therapeutic Equivalence Evaluations". Briefly, this document is called the Orange Book.

Actually, the above approaches to assessing the therapeutic equivalence of drugs from specific manufacturers are reflected by the FDA in this publication. FDA experts point out that the use of appropriate therapeutic equivalence codes can serve as a guide when replacing one drug with another and help, in particular, to reduce the cost of treatment. It must also be remembered that the main value of the FDA Orange Book is that it has an electronic version and is updated daily.

It should be noted that at present, in domestic terminology, a situation has developed when the bioequivalence test means only the study of the concentration profile medicinal substance, i.e. pharmacokinetic studies. And domestic experts believe that bioequivalence and therapeutic equivalence cannot be equated, since the latter can only be confirmed by conducting full-fledged clinical trials according to the protocol. Foreign documentation implies or directly indicates the identity of these concepts. Therefore, in the FDA Orange Book, the therapeutic equivalence mark can be placed on the basis of positive result when studying bioequivalence by pharmacokinetic approach. The self-sufficiency of such studies in most cases is due to the fact that the concentration profile of the drug substance in blood plasma corresponds to that at the site of action.

Some of the FDA's therapeutic equivalence criteria are also discussed below. But in general, we believe that the FDA's approach to solving the problem of drug interchangeability is quite reasonable and the most developed. But with the obligatory fulfillment of all the above conditions. We emphasize that the codes of therapeutic equivalence can serve as a guide in the directions of "efficacy" and "safety" if the problem in the direction of "quality" is solved.

Therapeutic Equivalence and GMP

By establishing criteria for therapeutic equivalence (i.e., interchangeability) of drugs, the FDA indicates the need for their production to comply with GMP requirements. This is certainly very important. Indeed, if drugs are not produced according to GMP standards, they cannot be homogeneous from batch to batch. And this affects all parameters of the drug: quality, efficacy and safety. Therefore, the proven therapeutic equivalence for one series of such products does not mean at all that all products in the future will meet the necessary bioequivalence standards.

At the same time, it must be understood that state control quality does not solve the problem as a whole, even if it could be done for all manufactured and imported drugs. Therefore, at present, all over the world and in our country we are talking on shifting the focus from drug quality control to quality assurance. Earlier, we have repeatedly pointed out that the manufacturer has high-quality drugs at the output when they are obtained as such in the production process, and not because low-quality ones are well rejected. Following this principle entails full compliance of the enterprise with GMP requirements (and even more), the introduction of the institution of authorized persons, the involvement of exclusively qualified personnel, the reduction of the acute shortage of specialists (technologists, analysts, etc.), and much more.

Here we also add that the manufacturer's own research and development resources play an important role in ensuring the quality of medicines. And the more these resources are developed and interact more closely with the production, control and quality assurance departments, the more you can be sure of the quality of the corresponding products.

Establishing equivalence without research

The starting position is that if the drug is intended for systemic use(the drug substance is determined in the systemic circulation), then pharmacokinetic bioequivalence studies are necessary. If the effect of the drug is not due to the appearance active substance in the systemic circulation or it is difficult to determine it there by the available analytical methods, then pharmacodynamic or even full-fledged clinical studies are needed.

But the question arises of comparing, for example, injectables. If these are ready-made solutions that are pharmaceutically equivalent drugs and intended for intravenous administration, then how to establish their therapeutic equivalence and should it be done at all?

According to WHO, generic drugs can be considered therapeutically equivalent without additional studies in the following cases.
1. Medicinal products are intended for parenteral (intravenous, subcutaneous or intramuscular) administration and are aqueous solutions of the same active substance in the same molar concentration, and also contain the same or similar excipients in approximately the same concentrations. Certain excipients (e.g. buffering agents, preservatives and antioxidants) may differ under the following condition: if it can be shown that this does not affect the safety and/or efficacy of the medicinal product.
2. Medicines are solutions for oral administration(e.g. syrups, elixirs, tinctures) containing the same active substance in the same molar concentration and essentially the same excipients in comparable concentrations. In this case, close attention should be paid to the consideration of those excipients that affect the absorption and stability of the active substance in the gastrointestinal tract.
3. Medicinal products are powders for the preparation of solutions, and the resulting solutions must meet the criteria specified in points 1 or 2.
4. Medicines are gases.
5. Ear and eye medicines that are aqueous solutions and containing the same active substance(s) in the same molar concentration and essentially the same excipients in comparable concentrations. Certain excipients (e.g. preservatives, buffering agents, osmotic and viscosity correctors) may differ, provided that their use should not affect the safety and/or efficacy of the product.
6. Medicines for local application, which are aqueous solutions and contain the same active substance (substances) in the same molar concentration and essentially the same excipients in comparable concentrations.
7. Medicinal products that are aqueous solutions for use as inhalations in a nebulizer or as nasal sprays, intended for use using essentially the same devices and containing the same active substance (substances) in the same concentration and , essentially the same excipients in comparable concentrations. Medicinal preparations may contain various excipients, provided that their use should not affect the safety and/or efficacy of the preparations.

Thus, the above situations remove the need for appropriate research. And the absence of the influence of excipients differing in composition in these cases, the applicant, obviously, must demonstrate by providing additional information. In general, one must understand that the guarantee of the therapeutic equivalence of the medicinal product in the described cases will be the compliance of its quality with the requirements of regulatory documentation.

Individual issues requiring attention

When using drugs, when purchasing them under government contracts, I would like to have a clear guide that would spell out which drugs are interchangeable. Such a guide could be an analogue of the Orange Book. But in its formation and in the establishment of the relevant rules, it is required to take into account a lot of specific points, in addition to those described above. general rules. Let us dwell on some particular problems.
INN. It is known that placing an order for the supply of medicines should be carried out according to INN. The exceptions are insulins and cyclosporine, for which this can be done by trade names. But it should be noted that the INN (or another name if the INN is missing) cannot serve as the only guideline.

Firstly, drugs with one active substance (INN) may differ in other characteristics (dosage, dosage form, method of administration), which generally excludes their interchangeability.
Secondly, with a formal approach, there is a possibility of making a mistake, since the WHO assigns INN (and this is taken into account in the State Register of Medicines of the Russian Federation) usually for acids and bases (if any). For salts, esters and other derivatives of the basic structure, INNs can only be assigned if such derivatives are the only possible option. For example, the INN for salt was assigned - metamizole sodium. And this was done for the reason that metamizole does not exist in the form of an acid due to instability, but this is a rare case. When making a decision, the error may lie in the fact that for one INN there may actually be different active substances, for example: ciprofloxacin (in the form of a base) and ciprofloxacin hydrochloride (salt), hydrocortisone (main structure) and hydrocortisone acetate (ester - derived from the base structures). As we mentioned above, preparations containing various salts and esters are pharmaceutical alternatives. FDA experts do not consider such drugs therapeutically equivalent, and this must be agreed, because in the general case, chemical modifications of active substances are aimed at changing solubility, stability, crystallinity, particle size, bioavailability, etc., which ultimately affects safety. and drug efficacy.

Replacing the dosage form. A radical change in the dosage form can have a negative effect in general. For example, drugs for parenteral and oral administration are not equivalent and are not interchangeable. Moreover, the patient may be unconscious and require injections. May require medication for rectal administration because the patient cannot swallow. Preparations for local and systemic use, even if they are used to treat the same pathology, have completely different effectiveness (systemic ones are more effective).
It is known that drugs with different routes of administration can generally be used according to different indications. A textbook example is fenoterol. The drug Berotek, a solution or aerosol for inhalation, is a bronchodilator (for example, to relieve attacks of bronchial asthma), and Partusisten, tablets or concentrate for infusion, is a tocolytic (prevention of preterm labor).

It should also be noted here that the number of units of the dosage form in the package can also be important. For example, birth control pills. One pack contains 21 tablets. The other contains 28 tablets, of which 7 are placebos. The FDA does not consider these drugs to be therapeutic equivalents.

Pharmaceutical alternatives are injectable powders to be dissolved, concentrated injectable solutions to be diluted, and ready-to-use injectable solutions that do not require such preliminary manipulations. Such drugs, according to the FDA, are also not therapeutically equivalent.

Combined drugs. The problem is the replacement of the combined drug with monopreparations containing the same active ingredients and in the same dosages as in the combination. For example, in the “Overview of the practice of considering complaints about the actions (inaction) of a customer, an authorized body, a specialized organization, an auction commission during bidding in the healthcare sector in accordance with the provisions of Federal Law No. 94-FZ of July 21, 2005” (prepared by the Control Department placing the state order of the Federal Antimonopoly Service of Russia, July 2011) states that “in the procedure for the formation by the Customer of lots for the purchase of antiviral drugs: combined and single drugs intended for the treatment of persons infected with the human immunodeficiency virus, it must be taken into account that combined and single drugs in the same combination in the form of 2 or 3 tablets are interchangeable. If we accept that this is acceptable, then the solution to this problem should be specific, i.e. be accepted for each drug on the basis of scientific evidence, taking into account the above criteria for therapeutic equivalence.

Dura lex…

Activities related to drugs are regulated by law. This applies incl. and procurement of drugs under government contracts. For example, according to Federal Law No. 94-FZ (part 3.1, article 34), “Auction documentation cannot contain an indication of service marks, trade names, patents, utility models, industrial designs, appellation of origin or manufacturer’s name, and also requirements for goods, information, works, services, if such requirements entail limiting the number of participants in placing an order.

But, as noted by the specialists of the Garant company, “it must be remembered that the purpose of placing an order is to satisfy the needs of the customer (Article 3 of Law No. 94-FZ). As noted in this regard, the courts, depending on their needs, the customer must establish specific requirements for quality, functional characteristics (consumer properties) of the product, dimensions, packaging, i.e. the needs of the customer are the determining factor in establishing the relevant requirements (decree of the Federal Antimonopoly Service of the West Siberian District of 07.09.2010 in case No. A03-2442/2010)”. And the question of the legitimacy of specifying specific requirements for a medicinal product, in our opinion, should be decided taking into account medical aspects which are discussed above.

Known, for example, is the situation that developed in 2010 when purchasing a preparation of zoledronic acid. When placing an order, the Ministry of Defense of the Russian Federation specified the dosage form and concentration of the drug in such a way that it actually indicated the drug of a specific manufacturer - the 5 mg / 100 ml infusion solution is produced only under the name Aklasta and is manufactured by Novartis. In this case, the Federal Antimonopoly Service made a decision about the violation, which limits the number of participants in the placement of orders, and the customer was issued a corresponding order. The FAS decision was appealed by the Ministry of Defense in arbitration court two instances, but upheld. In this case, no objections were received from the drug manufacturer, i.е. he agreed that a lyophilisate or concentrate for solution for infusion, which is also available on the market, would in this case be an equivalent replacement for the prepared solution, although, according to FDA requirements, this is not the case.

And here is another, it would seem, a similar situation, on which a different decision was eventually made. In 2010 Kurgan regional clinical Hospital placed an order for the purchase of a drug containing docetaxel. At the same time, additional requirements were included in the auction documentation: 1) concentrate for solution for infusion 20 mg, vial volume 24.4 mg/0.61 ml, complete with solvent 1.98 ml in vial No. 1; 2) concentrate for solution for infusion 80 mg, bottle filling volume 94.4 mg / 2.36 ml, complete with solvent 7.33 ml in bottle No. 1. Such detail, in fact, again pointed to a specific drug - Taxotere. Moreover, the customer did not hide this: according to Law No. 94-FZ, in the auction documentation he indicated not only the INN, but also the trade name with the obligatory words “or equivalent”. Nevertheless, the FAS found a violation, since there is actually no equivalent with this form of release on the market, but there are other drugs that could be a substitute. However, when considering the case in the arbitration court, the FAS decision was declared invalid.
A completely unexpected turn, which even to a specialist, at first glance, seems strange. But the scientific justification on which the court was guided was as follows. Quote: “... the contested decision of the Federal Antimonopoly Service for the Kurgan region is illegal due to the following: the interested party did not take into account that the requirement specified in the auction documentation for the volume of filling the vial is 24.4 mg / 0.61 ml and 94.4 mg / 2 ,36 ml is the only possible filling to ensure the effective use of the drug required by the Customer, who believes that it is this filling that ensures the proper dosage, taking into account adhesion (settlement on the walls of the vessel) of the drug and allows compensating for fluid losses during the preparation of a pre-mixed solution, believes that an excess of the drug in the vial guarantees, after dilution of its contents, the correct dose of 20 mg indicated on the vial label. Filling the vial differently as a result of adhesion will result in an actual dosage that will be lower than necessary, as a result, there will be no therapeutic effect when using the drug.

The same applies to the concentrate for the preparation of infusions of 80 mg. Insists that only the filling volume of the vial supplied by the Applicant and indicated in the auction documentation (24.4 mg/0.61 ml and 94.4 mg/2.36 ml) allows for an accurate dosage without additional measurements, while a bottle of a different size creates a significant risk of erroneous dosage. Thus, the indication in the auction documentation of the volume of filling of the vial was actually intended to ensure the supply of the drug in the form in which it is possible to provide it. effective application in the treatment of patients with cancer, this circumstance was not taken into account by the Federal Antimonopoly Service for the Kurgan region when issuing the contested Decision.”.

The examples given once again indicate that even if there are some general guidelines, each specific case requires separate consideration. A certain analogue of the Orange Book can approach the solution of this problem, in which it can be indicated that one drug does not have interchangeable drugs, while the other does. But at the same time, you should understand that this is a huge job. In fact, this is a scientific work based on evidence.

Conclusion

When considering the issues of drug interchangeability, one should proceed from the fact that reproduced drugs containing the same active drug substance are not therapeutically equivalent, and therefore are not interchangeable. Their therapeutic equivalence must be proven for each drug from each manufacturer. This evidence should be based on evidence-based evidence and the specific decision to change a drug should be medically specific and may be based on the information provided in the appropriate guideline.

Once again, we draw attention to the fact that with an unresolved issue regarding the quality of manufactured drugs, incl. in relation to the State Pharmacopoeia, making decisions related to the interchangeability of drugs remains difficult.

Literature

1. Bioavailability of drugs: principles and problems. Report Scientific WHO Group No. 536. - Geneva: WHO, 1975.
2. GARANT EXPERT: GARANT-Maximum (electronic resource).
3. Assessment of the bioequivalence of drugs. Methodical instructions. – M.: FGU NTs ESMP, 2008.
4. Letter of the Ministry of Economic Development of Russia, the Ministry of Health and Social Development of Russia and the Federal Antimonopoly Service of the Russian Federation dated October 31, 2007 No. 16811-AP/D04, 8035-VS and /IA/20555.
5. Tentsova A.I., Azhgikhin I.S. Dosage form and therapeutic efficacy of drugs. - M.: Medicine, 1974. - 336 p.
6. Federal Law No. 61-FZ of April 12, 2010 "On the Circulation of Medicines".
7. Federal Law No. 94-FZ of July 21, 2005 "On placing orders for the supply of goods, performance of work, provision of services for state and municipal needs."
8. Kholodov L.E., Yakovlev V.P. Clinical pharmacokinetics. - M.: Medicine, 1985. - 464 p.
9. Approved Drug Products with Therapeutic Equivalence Evaluations, 31st ed., FDA, 2011.
10. CPMP/EWP/QWP/1401/98 Rev. 1/ Corr.: Guideline on the Investigation of Bioequivalence, EMA, 2010.
11. Directive 2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community Code Relating to Medicinal Products for Human Use.
12 Generic Prescribing in Epilepsy. Is it Safe? P. Crawford, W. Hall, B. Chappell et al., Seizure 1996; 5:1-5.
13. ICH Harmonised Tripartite Guideline: The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Quality M4Q(R1). – Geneva: ICH, 2002.
14. ICH Harmonised Tripartite Guideline: The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Safety. M4S(R2). – Geneva: ICH, 2002.
15. ICH Harmonised Tripartite Guideline: The Common Technical Document for the Registration of Pharmaceuticals for Human Use: Efficacy. M4E(R1). – Geneva: ICH, 2002.
16. Joint Statement between The International Pharmaceutical Federation (FIP) and the International Federation of Pharmaceutical Manufacturers Associations (IFPMA): Ensuring Quality and Safety of Medicinal Products to Protect the Patient. – Barcelona: FIP, IFPMA, 1999.
17. WHO Technical Report Series, no. 902, 2002. Annex 11: Guidance on the Selection of Comparator Pharmaceutical Products for Equivalence Assessment of Interchangeable Multisource (Generic) Products.
18. WHO Technical Report Series, no. 937, 2006. Annex 7: Multisource (Generic) Pharmaceutical Products: Guidelines on Registration Requirements to Establish Interchangeability.

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

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

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

According to the WHO definition, the term “generic” is understood to mean 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 a patent or other exclusive rights.

A generic product must meet the following criteria:

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

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

EU Directive 2001/83 also defines the substantive similar drugs. A medicinal product is essentially the same as the originator product if it satisfies the criteria for the same quantitative and quality composition regarding active substances, the same dosage form and is bioequivalent, unless it is scientifically obvious that it differs from the original drug in terms of safety and efficacy.

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

The international community, national health services are interested in developing and putting into practice evidence-based criteria for evaluating the effectiveness and safety of generic drugs that are produced by various companies.

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

In Europe, medicines are considered to be pharmaceutically equivalent, if they contain similar active substances in the same quantity and in the same dosage form, meet the requirements of the same or similar standards.

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

But pharmaceutically equivalent agents will not necessarily be therapeutically equivalent, ie. such, after the use of which in the same molar dose, the effect in terms of efficacy and safety is actually the same. Thus, erythromycin, registered in the Russian Federation, when administered intravenously with a high frequency, caused thrombotic complications, while in Europe, Abbott erythromycin is widely used for intravenous administration, while being considered the safest macrolide antibiotic for intravenous infusion.

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

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

The definitions adopted in the countries of the European Union (EU) and in the USA are somewhat different.

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

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

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

At the same time, it is important to note that it is impossible to talk about the bioequivalence of drugs if it is not known for sure where and how the drug was produced. If there is no certainty that the production site where this drug is manufactured complies with GMP requirements, it is pointless to engage in bioequivalence studies, as well as other clinical trials, because the quality of drugs is not maintained from batch to batch. In a global sense, GMP is a step-by-step, systematic and step-by-step "embedding" of quality in a drug. In this regard, bioequivalence testing is only part of the overall system for ensuring the quality of medicines.

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

In 1984, the President of the United States signed a law requiring the FDA food products medicines) to make the list of approved prescription and over-the-counter medicines publicly available. This law introduced for the first time a new assumption that bioequivalent drugs are therapeutically equivalent and therefore interchangeable. Edition Approved Drug Products with Therapeutic Equivalence Evaluations- a list called "Orange Book" (Orange Book), - identifies drugs approved by the FDA based on their safety and efficacy. Speaking about the status of the Orange Book, it should be noted that by informing about its assessment of the therapeutic equivalence of drugs using the list, the FDA offers its recommendations to the public, specialists and authorized bodies on the choice of a drug. Such an assessment should not be taken as a ban on the use of a particular drug, or as evidence that one of them is preferable to another. The Orange Book does not mostly serve to distinguish multisource medicines from each other, but informs whether the available tools have solved the problem of proving their therapeutic equivalence to the reference product or not. Therapeutic equivalence is a scientific judgment, while the cost-saving practice of generic substitution is also based on social and economic considerations.

The Orange Book came about because, in order to save money in the healthcare system, virtually every state in the United States has enacted laws and/or regulations to encourage generic substitution. The implementation of these laws required the creation of a positive or negative list of drugs (those that either can or cannot replace the original drug). FDA experts have created a single drug formulary, in which the assessment of therapeutic equivalence of drugs was presented in the form of a letter code. The system of letter codes describing therapeutic equivalence allows you to quickly determine whether a certain drug has been established to be bioequivalent to the reference one (first letter) and to obtain additional information about the FDA assessment (second letter). The two main categories into which generic drugs can be classified are labeled A and B. Category A includes drugs that are therapeutically equivalent to other pharmaceutically equivalent products for which:

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

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

At one time, the FDA published a draft guide on the activities of pharmaceutical companies, as well as enterprises that were owned or influenced by distributors (so-called sponsors) of medical products. The need for public hearings and discussion of the draft was due to the fact that individuals and groups of people approached state legislatures, pharmaceutical organizations, and drug control committees, expressing concern about the problem of interchangeability of some drugs, in particular drugs with limited therapeutic index. They were especially interested in whether the safety and efficacy of such drugs would change if, instead of a drug from a well-known manufacturer, a drug recognized by the FDA as therapeutically equivalent, but not protected by a registered trademark, was replaced. In 1998, a letter from FDA Health Commissioner Stuart L. Nightingale was published to clarify this issue. Below is his summary: “Based on the determination of therapeutic equivalence for drugs, the FDA has issued a statement:

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

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

a) their effectiveness and safety have been proven;

b) they are pharmaceutically equivalent, namely:

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

c) are bioequivalent, namely:

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

d) adequate instructions in the instructions;

e) manufactured in accordance with GMP requirements.

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

Thus, therapeutic equivalence is a basic requirement for drug interchangeability.

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

It is believed that if the bioequivalence of drugs is proven, there is no need to conduct additional clinical trials of generic drugs, since the presence of bioequivalence indicates that all efficacy and safety indicators of the study drug are comparable. Bioequivalence trials are clinical studies in healthy volunteers or patients who are indicated for the administration of an investigational medicinal product.

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

The 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. However, it is also possible other approaches, namely:

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

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

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

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

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

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

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

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

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

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

Consequently, significant discrepancies in the properties of branded and generic drugs are possible. For example, with bioequivalence values ​​below 100%, the drug may not be effective. On the contrary, with an increase in the considered indicator, an increase in the number of side effects should be expected. Of particular concern are drugs with a low therapeutic index (the difference between the minimum effective dose of the drug and its maximum toxic dose) - digoxin, phenytoin, carbamazepine, cyclosporine, warfarin. This situation requires tightening and expanding the requirements for pharmacokinetic studies. The issue of reducing differences in parameters to 10-15% is being discussed, which will reduce the number of drugs with borderline pharmacokinetic parameters.

Another limitation imposes on the use of bioequivalence test results the existence of drugs (sertraline, fluoxetine, chlorpromazine, clozapine) with significant variability in pharmacokinetic parameters, which depends, in particular, on the complexity of drug metabolism processes (cytochrome system, the presence of several excretion routes, etc. .). Such variability can be "intra-individual" in nature. In one case, it is associated, for example, with the genetic polymorphism of cytochromes, which is observed in different population populations, in the other, with the functional state of these enzymes, which changes in the same person under the influence of various external factors (for example, the use of grapefruit juice). Therefore, the results of a bioequivalence test performed on a small group of volunteers who consumed a similar diet may not be valid for real clinical conditions.

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

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

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

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

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

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

The objections discussed are not merely theoretical considerations. There is a lot of information in the relevant publications about the results of bioequivalence cross-checking. various drugs. These data indicate that a significant proportion of generics fail such testing. So, held in the UK in 1995-1996. an analysis of 2427 generic drugs found 228 significant differences. No less striking data was obtained in the United States. The FDA has found that up to 20% of branded and generic drugs available in the country are not bioequivalent and therefore cannot be used interchangeably.

Examples of clinical non-equivalence of enalapril preparations are given. It has been shown that the clinical efficacy in achieving the target level of blood pressure in patients with arterial hypertension of 4 generic enalaprils well-known manufacturers was lower than that of the original drug (Renitek, MSD). The generics studied were pharmacokinetically equivalent to Renitec. Based on the results obtained, the authors concluded that the therapeutic equivalence of generic enalapril preparations is not the same.

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

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

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

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

The literature presents the results of a comparison of branded and generic clozapine (Clozaril, Novartis Pharmaceuticals and clozapine, Zenith Goldline Pharmaceuticals). In the course of the study, it was found that the discrepancy between these psychotropic drugs in terms of pharmacokinetic parameters is observed in 40% of patients suffering from schizophrenia.

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

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

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

In a recent survey of 301 neurologists working in the United States, 204 (67.8%) of them experienced a recurrence of seizures and 168 (55.8%) reported an increase in side effects when switching from brand-name antiepileptic drugs to generic ones. .

We describe 11 cases in which, after replacing branded lamotrigine with its generics, control over epileptic seizures was lost.

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

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

Another paper, published in the American Journal of Cardiology in May 2000, cites the opinion of 64 electrophysiological experts, members of the North American Society for Electrophysiology Stimulation, who report 32 cases of recurrent arrhythmias (ventricular fibrillation, ventricular tachycardia, atrial fibrillation and atrial tachycardia) during replacing the branded antiarrhythmic drug amiodarone (Cordaron, Sanofi-Synthelabo) with its generics.

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

Speaking of chronic diseases, it should be noted that many of them tend to recur. In view of this, modern recommendations provide for long-term maintenance therapy along with stopping therapy. In practice, there is often a situation when stopping therapy, which is most often carried out in a hospital, is carried out with an original drug. In the future, after the patient is discharged, this drug, due to "economic" considerations, is often replaced by its generic drug. In the light of the data presented above, it is obvious that the substitution in question is possible only if there is confidence in the pharmaceutical, pharmacokinetic and therapeutic equivalence of the original and generic drugs.

There are reports that the introduction of generic drugs into the pharmaceutical market does not always lead to lower direct health care costs. A recent Canadian study analyzed that the 11% difference in relapse rates between generic and brand-name clozapine negates the cost advantage of generic clozapine. Similar data were obtained for antiepileptic drugs.

The above data, like many others, according to the chief clinical pharmacologist of the Ministry of Health of the Russian Federation, Professor Yu.B. Belousov, dispel the myth about the cheapness of generic drugs, since the costs of their use are much higher than when using original drugs. Contrary to popular belief that generic medicines reduce direct costs of treatment, promote competition and lower prices for branded drugs, and even are one way to introduce cost-effective medical technologies into clinical practice, some recent research suggests otherwise.

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

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

The list of references is in the editorial

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

N.P.Kutishenko1, S.Yu.Martsevich1,2, I.V.Vashurina1
1FGU GNITs PM of the Ministry of Health and Social Development of Russia, Moscow
2Department evidence-based medicine First MGMU them. I.M. Sechenov

The problem of the effectiveness and safety of drugs-copies (generic drugs, generics) continues to worry scientists, doctors, and the public. She is constantly addressed at scientific conferences and symposiums, in the media, special scientific studies are devoted to her, in which sometimes thousands of patients participate, for example, the ORIGINAL study (Evaluation of the effectiveness of the transfer from Indapamide Generics to Arifon retard in patients with arterial hypertension) . And all this despite the fact that the scientific part of this problem has been basically solved long ago in numerous studies, and its practical part is reflected in a number of regulatory documents, which will be discussed below. It is characteristic that publications devoted to the comparative evaluation of original drugs and generics are now extremely rare in the foreign scientific literature, although quite recently there have been much more such publications.

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

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

What is a generic (generic drug)

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

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

The WHO defines the therapeutic equivalence of an originator drug and a generic (multisource pharmaceutical product) somewhat differently. In accordance with WHO requirements, two pharmaceutical products are considered therapeutically equivalent if they are pharmaceutically equivalent (or pharmaceutically alternative) and, after administration at the same molar dose, their effect in terms of efficacy and safety is exactly the same for the same route of administration and for the same indications. This must be demonstrated by appropriate bioequivalence studies such as pharmacokinetic, pharmacodynamic, clinical or in vitro studies.

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

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

Regarding the issue of confirmation of therapeutic equivalence, there are certain contradictions with the FDA rules, and there are also no documents defining the procedure for conducting and criteria for evaluating the results of such clinical trials. If we turn to the time-tested FDA rules for determining therapeutic equivalence, then five conditions must be met without fail: 1) drugs must be recognized as effective and safe, 2) they must be pharmaceutically equivalent, including compliance in terms of the number of active ingredients, their purity, quality, identity, 3) comply with bioequivalence standards and with the participation of at least 24-36 volunteers in the study, 4) are correctly labeled and, last but not least, 5) are produced in accordance with the requirements of GMP (Good Manufacturing Practice) .

Significance of Therapeutic Equivalence Studies

However, despite the importance of bioequivalence indicators in the registration of a generic drug, the results of clinical trials to prove equivalence retain a certain significance. To a greater extent, this applies to analogues of pharmaceuticals of biological origin (the so-called biosimilars or biogenerics). For them, therapeutic equivalence studies are one of the conditions for registration. In the near future, such drugs will increasingly appear on the pharmaceutical market, since the validity of patents for a number of original biological products (including low molecular weight heparains) is expiring. In this regard, some generic companies have begun to develop the production of biosimilars, despite the fact that the chemical structure and technology for producing biosimilars is much more complicated than traditional chemical drugs. Since biosimilars have a complex three-dimensional spatial structure, it is rather difficult to accurately characterize their quantitative content in biological fluids; therefore, it is generally accepted that conventional bioequivalence studies are clearly not enough for such drugs. This forces regulatory authorities to require manufacturers of biosimilars to conduct both preclinical (toxicological, pharmacokinetic and pharmacodynamic) and clinical studies (complete presentation of data on the efficacy and safety of the drug), as well as data on the study of immunogenicity. Preparations of biological origin include hormones, cytokines, blood coagulation factors, monoclonal antibodies, enzymes, vaccines and preparations based on cells and tissues, etc.

"Generic replacement"

It should be noted that differences in the therapeutic effect of original drugs and generics or different generics among themselves, in principle, are allowed by a number of international documents. Quite a long time ago, the term "generic replacement" was introduced, which is understood as the release of a medicinal product, commercial name which differs from that prescribed by a doctor, and the chemical composition and dosage of the active principle are identical. The documents of the World Medical Assembly warn that when dispensing drugs that are not completely identical in chemical composition, biological effect or therapeutic efficacy, the patient may experience an inadequate effect, i.e. With adverse reactions or with insufficient therapeutic efficacy. This document draws particular attention to the fact that public services control should inform doctors about the degree of chemical, biological and therapeutic identity of drugs manufactured by one or different manufacturers, and the quality control services that exist at drug manufacturing enterprises are required to monitor the steady compliance of manufactured drugs with chemical and biological properties standards.

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

What should a practitioner be guided by when choosing generic drugs?

A simpler question also arises: what should practitioners do when choosing a drug, especially in cases where this therapy is long-term and the quality of which may affect the fate of the patient, for example, in the secondary prevention of cardiovascular complications in cardiac patients high risk. On the one hand, all regulations, as well as economic feasibility, make the doctor use the generic in the first place (if it is registered). On the other hand, a number of well-designed clinical studies (uncontrolled studies do not count) indicate that not all generics are full-fledged copies. Pharmaceutical companies skillfully use these facts, claiming that all generics are defective drugs and, using them, the doctor deliberately prescribes less effective therapy.

Most Russian specialists, recognizing the above facts, conclude that it is necessary to conduct direct comparative studies to study therapeutic equivalence with those generics that are already registered and most often prescribed in the clinic. made with generics in Russia.

Thus, on the one hand, there is no reason to doubt that the creation of a generic - a complete copy of the original drug - is absolutely possible. However, certain deviations in the development and production of a generic can affect its quality. Ideally, these deviations should be recorded by the entire preclinical control system, however, in practice, apparently, this system is not always clearly observed, which leads to the appearance of incompletely equivalent generics. In such cases, the only way to confirm the quality of a generic is to conduct methodically well-designed comparative clinical trials to study therapeutic equivalence. The results of such studies will also provide a more accurate answer to the question of the rationality of the intervention, both in terms of cost-effectiveness and its accessibility.

Bibliography

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