Replacing original drugs for generics: bioequivalence and therapeutic equivalence of various salts of amlodipine. Studying the range of eye drops Names Selected problems requiring attention
1. Interchangeability of drugs for medical use is determined in the manner prescribed by the Government of the Russian Federation, on the basis of the following parameters:
1) equivalence (for bioanalog (biopoidal) drugs (bioanalogs) - 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 drugs, if during the study of the bioequivalence of the drug or in case of the impossibility of carrying out this study, when conducting a study of the therapeutic equivalence of the drug, the lack of clinically significant differences in pharmacokinetics and (or) safety and efficiency of the drug for medical use);
2) the equivalence of the dosage form (under equivalent dosage forms are different dosage forms that have the same method of administration and method of use with comparable pharmacokinetic characteristics and pharmacological effects and ensuring the achievement of the necessary clinical effect. Differences of dosage forms are not an obstacle for their interchangeability, if Conducting the study of bioequivalence of the drug or in case of impossibility of conducting this study during the study of the therapeutic equivalence of the drug, the lack of clinically significant differences in pharmacokinetics and (or) safety and efficacy of the drug for medical use);
3) the equivalence or comparability of the composition of the auxiliary substances of the drug for medical use (the differences in the composition of the auxiliary drugs of the drug for medical use are not an obstacle to their interchangeability, if during the study of the bioequivalence of the drug for medical use or in case of impossibility of this study during the study The therapeutic equivalence of the drug for medical use is proved the absence of clinically significant differences in pharmacokinetics and (or) safety and efficiency of the drug for medical use. At the same time, the differences in the composition of the aids should not lead to the risk of serious unwanted reactions in individual groups of patients or an increase in the frequency of their occurrence. );
4) identity of the method of administration and application;
5) the lack of clinically significant differences in the study of the bioequivalence of the drug or in case of the impossibility of conducting this study, the lack of clinically significant differences in the safety and effectiveness of the drug during the study of therapeutic equivalence. This parameter is not applied to the reproduced drugs specified in paragraph 10 of Article 18 of this Federal Law. In relation to bioanalog (biopoidal) drugs (bioanalogs), data on the absence of clinically significant differences in the safety, efficacy and immunogenicity of the drug based on the results of clinical studies are provided in the manner prescribed by this part;
6) Compliance of the manufacturer of the medicinal product with the requirements of proper production practices.
2. Comparison of the parameters of the recorded drugs for medical use is carried out by the Commission of Experts Expert Institutions during the examination of such drugs in the process of their state registration. The findings of experts on interchangeability or non-viability of drugs for medical use, made as a result of this comparison, are made in the form of annex to the conclusion of experts in the form approved by an authorized federal executive body.
3. The provisions of this article do not apply to reference drugs, medicinal plant preparations, homeopathic drugs and drugs that are permitted for medical applications in the Russian Federation for more than twenty years and in respect of which it is impossible to conduct a study of their bioequivalence.
ACTUAL TOPIC
Equivalence of reproduced drugs: pharmaceutical aspects
A. P. Arzamastese, V. L. Dorofeev
Moscow Medical Academy. I. M. Sechenov
Test "Dissolution"
Pharmacokinetic tests are quite expensive and long. Therefore, in recent years, the question of applicability has been actively discussed for the establishment of bioequivalence of generics well-known from the pharmacopoeial test "Dissolution".
Of course, there is a problem of correlation between the results of experiments conducted iN. vitro. and iN. vivo, since this correlation is not always detected. Moreover, despite explicit differences in the release rate iN. vitro., significant differences in bioavailability may not be detected, and vice versa - the same test indicators "dissolution" do not always determine the bioequivalence of generics. Nevertheless, it is known that in the case of therapeutic non-equivalence of drugs, there is often a difference in the release rate of the active substance from the dosage form, which gives reason to apply the dissolution test as an alternative to pharmacokin-native tests.
For solid oral dosage forms (pills, dragees, capsules, granules), the dissolution test is one of the most important quality criteria. In fact, its use when analyzing the medicinal
ACTUAL TOPIC
the drug is an attempt to introduce a test in ND, which, along with the assessment of pharmaceutical equivalence, would allow at least an approximate estimate of bioequivalence.
It is known that two groups of factors affect the release of the medicinal substance.
1. Physico-chemical properties of Subsen
.
Solubility of the substance.
Particle size substance.
Crystalline state of substance.
forms.
Manufacturing technology.
Excipients.
In accordance with these criteria, 4 groups of substances are distinguished:
Well dissolved and well absorbed.
Poor dissolve and well absorbed.
Well dissolved and poorly absorbed.
Poorly dissolve and poorly absorbed.
The drugs of the 2nd group are classic objects for research on the test "Dissolution", since it is for them that producing technology is the most important: particle size of substance, its crystalline state, type and properties of the dosage form.
6 www.. fDA. gOV..
At the same time, the question arises about the need to use the "dissolution" test for the substances of the 1st and 3rd groups. The properties of the dosage form, the particle size and the crystalline state of the substance in this case are not so much affecting the release of the actual substance. Moreover, in the 1st group there are no "bottlenecks". However, the FDA in this case indicates that the test is worth carrying out, and if the active substance is released in 15 minutes by at least 85%, then we can say that the dissolution does not affect bioavailability, since the defining factor in this The case will be the speed of emptying the stomach.
Regarding Correlation Test iN. vivo and iN. vitro. FDA indicates that such a correlation is more likely to be found for the 2nd group and with a smaller - for the 1st and 3rd.
Next, the following question arises: and whether the tests are "dissolution" tests carried out within NDs sufficient that according to their results it was possible to conclude on bioequivalence? Evaluation of drugs in the Dissolution test in pharmacopoeial analysis is carried out at one time point. This is usually 45 minutes, unless otherwise specifically specified in ND on a specific drug. Near the authors it was shown that for comparing generics, the analysis at one point is insufficient. This analysis gives an approximate representation only about the degree of release of the active substance. Moreover, each manufacturer in accordance with the general pharmacopoeial requirements of the Waves independently choose the dissolution medium and the speed of rotation of the agitator or baskets. And if he fails to produce a qualitative generic (bioequivalent to the original drug), then it can simply increase the mixing speed to achieve the notorious 70% dissolution in 45 minutes.
Therefore, when using the dissolution test, several time points should be obtained to evaluate bioequivalence, on the basis of which the release curve is built, and to conduct a study of the test drug and the preparation of comparison in the same conditions. In WHO recommendations, it is indicated that in some cases a comparison of the dissolution profiles of the subject and the original drugs can serve as a basis for conclusion on their bioequivalence.
Another question: when to establish bioequivalence can be limited to
Vedomosti NTS ESMP, 1, 2007
dissolution test? WHO recommends to navigate, first, at the dissolution rate: you can not carry out pharmaco-kinetic studies if the drug is very fast (at least 85% in 15 minutes) or quickly (at least 85% in 30 minutes) is released from the dosage form. Secondly, the similarity of the releases of the subject and original drugs should also be proved (except for the case of "at least 85% in 15 minutes" - see further).
In pharmacokinetic studies, the curve must contain at least 2 points for the increasing phase of the concentration and at least 5 for the phase of its decline. On the dissolution curve, the concentration is only increasing, so the number of points should be chosen depending on which drug is analyzed and which medicinal substance it contains. For drugs of the 1st and 3rd groups, FDA recommends sampling every 5-10 minutes. This means that when analyzing drugs with unmodifable release for 60-70 minutes, at least 6 points should be on the dissolution curve. To compare the two dissolution profiles, 12 units of the subject and 12 units of original drugs are needed.
To compare the release profiles, the FDA recommends using, in particular, the model-independent method by calculating two parameters: the difference factor (/,) and the factory factor (f. 2 ) .
The difference factor shows the difference between curves in percentage and is calculated according to the following formula:
I iv.C.
h.100,
A \u003d. L.
Z * R.
where: p -number of time points R. t. - release from the preparation of comparison at the point t., %;
T. t. - release from the subject's test at the point t., %.
The similarity factor estimates, respectively, the similarity of two curves in percentage and is calculated by the formula:
/, \u003d 50 x L g
t. = 1
It is believed that the difference between the curves is absent if:
the difference factor takes values \u200b\u200bfrom 0 to 15;
the factor of similarity takes values \u200b\u200bfrom 50 to 100.
the number of time points taken into account should be at least 3;
test conditions for both drugs should be the same and sampling should be carried out at identical intervals;
after reaching the level release of 85% of both drugs into account, all points are taken to this level and one next point;
the coefficient of variation for the first time point should be no more than 20% and for subsequent no more than 10%.
Plan:
1. Introduction
Biopharmacy as a new pharmacy referral direction.
The concepts of chemical, biological, therapeutic equivalents.
Biological and pharmaceutical availability of medicinal substances, methods of determination.
Pharmaceutical factors and their effect on the bioavailability of medicinal substances in various dosage forms:
Simple chemical modification of medicinal substances;
Physical condition of medicinal and excipients;
Excipients;
Dosage form;
Technological process.
1. Introduction
1.1. Biopharmacy- scientific direction that studies the biological effect of drugs, depending on their physicochemical properties, dosage form, manufacturing technology and some other factors.
As a new direction in pharmacy, biopharmacy appeared in the late 50s of the 20th century at the junction of related sciences: chemistry, biology, biochemistry, medicine. The term "biopharmacy" was first introduced in 1961 by the Foreigners of Biopharmacy, consider American scientists Levy and Wagner. The mid-XX century period is characterized by the introduction of highly efficient drugs from groups of antibiotics, sulfonamides, hypotensive drugs, sulfonamides into the medical practice of highly efficient drugs. Steroid hormones. When using these drugs that fully meet the standards, the phenomenon of "therapeutic non-equivalence" of drugs was found.
What denotes the term "non-equivalence" from a biopharmaceutical point of view?
1.2. There are chemical, biological and therapeutic equivalents.
Chemical equivalents are drugs containing the same medicinal substances in equal dosages, in the same dosage forms that fully meet the requirements of regulatory documentation, but made in various ways.
Biological equivalents- those chemical equivalents whose application provides the same degree of absorption (suction) of the drug, determined by the content of the drug in bioshydro.
Therapeutic equivalents- biological equivalents providing identical therapeutic effect on the same disease.
These concepts were formulated later.
2. Definition of therapeutic equivalence- Very difficult task. Therefore, in practice, the biological equivalence of the drug is more often determined. The measure of biological equivalence of the drug is biological accessibility (database). (Tensetova A.I., Dosage Form and Therapeutic Efficiency of Drugs. M., Medicine, 1974 p. 69).
The database is defined as a relative amount of medicinal substance that has reached the systemic blood flow and the speed with which this process occurs. Relative amount of substance, because The database is determined in comparison studieddosage form I. standard.In this case, the same doses of the standard and the examined dosage form are used. CBB express in%.:
where a is the amount of medicinal substance that has been in the body after appointment standard dosage form; B - the amount of medicinal substance that has been in the body after appointment studieddosage form.
Distinguish absoluteThe database, with the quality of the dosage form, the solution for intravenous administration is used as a standard dosage form. In this case, the method of administration, the entire dose of the medicinal substance enters a large circle of blood circulation.
In practice, more often determine relativeDatabase In this case, the standard is well sufficed to use a dosage form, for example, a solution or suspension for oral dosage forms (pellets, granules); Solution or suspension in the form of mineclism for rectal dosage forms (suppositories).
The database is determined by living organisms, i.e. In experiments « iN.vivo», - on animals when conducting preclinical tests, on the people of the bonovoles with clinical trials. Two groups of database definition methods are known: pharmacodynamic and pharmacokinetic.
Pharmacodynamic- based on measuring the effects caused by the drug substance, or biochemical reactions to the drug substance or its active metabolites. For example, a pupil reaction is recorded, changing heart rate, changes in pain or biochemical indicators after the administration of the drug.
More objective and less complex pharmacokineticmethods based on measuring the level of drug concentration in the blood depending on the time or its metabolites in the urine.
In pharmacokinetic methods for determining the database, a consistent fence of blood samples, urine and other bioseclauses for a certain time after the administration of the drug in samples with sensitive analytical methods determine the concentration of the drug substance.
More simple methods have been developed « iN.vitro.» (in the tube), allowing indirectly to determine the database at the speed and degree of release of the drug substance from the dosage form, or methods that simulate the absorption of the drug in vitro.
With the in vitro methods, the term database is replaced by the term "Pharmaceutical accessibility"(PD).
To determine the pharmaceutical accessibility, a variety of methods and devices are proposed.
Single-chamber devices with static dissolution conditions and using mixing means, for example, to determine the pharmaceutical availability of the medicinal substance in tablets, granules, dragees, capsules with solid content, use the test "Dissolution" using instruments "Rotating basket" and"Bladed mixer"(see the Office "Dissolution"),
To assess the pharmaceutical accessibility of medicinal substances in soft dosage forms, methods based on diffusion of medicinal substance from the dosage form are used:
dialysis methods (through membranes);
direct diffusion method in various environments: agar, collagen gels.
Problem interchangeability medicines (LS) is currently being discussed rather actively at various levels and in our country, and abroad. It has both purely therapeutic and fairly relevant economic background. It should be noted that in our country there is no clear definition of interchangeable LS. The interpretation of this concept very strongly depends on the opinions of various specialists and the experience of the use of HP. Completely different attitude towards this term may occur when solving purely therapeutic tasks and tasks related to the purchase of drugs in government contracts.
Nevertheless, we will concentrate on some specific aspects of interchangeability. From the therapeutic point of view, it is obvious that two different LS (i.e. containing two different active substances) of one pharmacological group can replace each other, provided that they have, for example, the same mechanism of action (say, the blockade of the same receptors) And that, if necessary, appropriate adjustment of doses and multiplicity of reception will be carried out. And in this sense, these two drugs for a doctor will be interchangeable: now there is no one for sale, and it will appoint another. This is the so-called therapeutic replacement, but it is not identical to the concept of interchangeability. Currently, this term concerns the replacement of the original LAN to generic or replace one generic to 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 are on the way to solve this issue, we will discuss in this article.
The problem of equivalence of reproduced LS (generics) is quite acute due to the large number of drugs of various manufacturers in the market. This question is relevant all over the world, but in our country in the past two decades he has gained special significance as we are not ready for a huge stream of drugs. Our regulatory system, scientific base and all the concepts were adapted for the market suffering from LS deficiency. Now the situation has changed dramatically. The Russian pharmaceutical market is saturated with a large number of drugs. According to some active substances (paracetamol, acetylsalicylic acid, sodium diclofenac, sodium metamizole, ENALAPRIL Maleat, ciprofloxacin hydrochloride, etc.) Another 10 years ago several hundreds of drugs of different manufacturers were registered (taking into account different dosage forms and dosages). Now the number of relevant drugs has decreased slightly, but this is a problem of generics in no way removes.
What is the question? After all, the excess of goods should contribute to competition, the struggle for the client by improving the quality of products and reduce its cost. And it is from this place in the future in this article we will try to avoid the words "product", because we will talk about LS, i.e. About products with unique properties for which the priority criteria are quality, efficiency and safety. Nevertheless, the rest is a consequence - both the price of drugs, and the health that we risk losing, using drugs that do not meet modern requirements.
Requirements for hp
Starting a discussion of approaches to the assessment of LS interchangeability, it is worth holding an excerpt from the joint statement of the International Pharmaceutical Federation (FIP, www.fip.org) and the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA, www.ifpma.org) adopted in 1999, Which, in particular, it is said that the replacement of the original LAN on the reproduced "should be carried out only when compliance with the adopted international standards, including bioequivalence, in order to guarantee the quality of all drugs in the market."
In the same document, it is indicated: "All governments should take steps to ensure the quality, safety and effectiveness of all LS available in the respective states, according to adopted international standards. This applies both to the original and the reproduced LAN, to the private and public sectors and to imported and produced in the local product market. "
Thus, there are three requirements for any LS: efficiency, security and quality. Such an approach to the estimate of drugs is currently accepted worldwide, incl. And in our country.
Categories "Efficiency" and "Safety" refer to medical and biological issues, and "quality" is a purely pharmaceutical problem and reflects the compliance of the LANs with the requirements of regulatory documentation on authentication (i.e., the identity of the contents of the package), purity (by impurities) and quantitative content of the active substance (or substances in the case of a combined drug). With the provision and quality control of drugs, the rules of proper production practice (GMP) are inextricably linked.
Original and reproduced LS. Major terms
When discussing issues of LS interchangeability, it is necessary to determine the main terms. In the Federal Law No. 61-FZ "On the circulation of drugs", the following definition is given: The original LS - HP, which contains the first time-obtained pharmaceutical substance or a new combination of pharmaceutical substances, the effectiveness and safety of which is confirmed by the results of preclinical research of drugs and clinical studies of drugs. In foreign literature, you can meet the corresponding terms "Innovator Product", "BRANDED PRODUCT". In WHO "Innovator Pharmaceutical Product", this is a product that first allowed to use on the basis of documentation on its quality, safety and efficiency.
The organization that has developed the original LAN receives patent protection for a long period (up to 20 years or more) to compensate for the high costs of developing the means and its promotion on the market, as well as get an additional income. Original HPs have a high cost during patent protection and higher cost compared to generics after its end.
This circumstance causes constant criticism. It is argued that the costs of the development of a new drug (i.e. a new molecule) are clearly overestimated by leading manufacturers, as unreasonably overestimated and the cost of original means after the end of the patent.
But do not forget that, firstly, modern LS have more subtle, directed, electoral mechanisms of action than funds, for example, from the same pharmacological groups, but developed several decades ago. Therefore, even with modern screening of active substances, which allows in some cases to significantly reduce the search for the new active molecule, the search period multiplied by the cost of the modern high technologies used, turns into significant financial costs.
Secondly, we will not be tired of repeating that manufacturers of innovative LS are the main locomotive of the pharmaceutical industry. It should be remembered that the profit obtained by the realization of the original drugs is ultimately sent to the development of innovative LS.
The reproduced LS - LS, which contains the same pharmaceutical substance or a combination of the same pharmaceutical substances in the same dosage form as the original LS, and entered into appeal after the origin of the original LAN. For reproduced drugs, the term "generic" or "generic" (Generic Product) also apply.
It should be noted that in WHO documents (www.who.int) in connection with various interpretation in different countries of the term "generic" it is recommended to use the term "multi-articular drugs" (MultiSource Pharmaceutical Products). WHO determines them as pharmaceutically equivalent or pharmaceutically alternative preparations that may or not be therapeutically equivalent. The term "multi-stroke", although not very frantic and non-parting in domestic terminology, but specifies the understanding that the reproduced LS is made from pharmaceutical substances and auxiliary substances that have the most different origin. That is, they are going like a designer, from the details of different manufacturers. Since theoretically suppliers can easily change, it is already a reason for criticism from the manufacturers of original drugs. Indeed, such an approach generally makes it difficult to provide homogeneous quality, as well as compliance with the requirements of efficacy and safety.
In this regard, it is interesting to define a generic, which is given in Directive 2001/83 / EC of the European Parliament, which determines the requirements for drugs: a generic drug (Generic Medicinal Product) means a drug that has the same qualitative and quantitative composition for the active substance and that The same dosage form as the drug comparison, and the bioequivalence of which was proven by conducting bioavailability research relative to the preparation of comparison. That is, the countries of the European Union theoretically do not allow for generics in the market with problems of bioequivalence, although, of course, this does not at all exclude the corresponding problem.
According to the determination of WHO, drug preparations are pharmaceutically equivalent if they contain the same number of one and the same active substance (substances) in the same dosage form, meet comparable quality standards and are intended for one way of administration. A similar, but more specific and convenient determination gives the FDA USA (www.fda.gov): preparations 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 one route of administration and (5) correspond to pharmacopoeial or other applied quantitative content, purity and authentication standards.
WHO indicates that drug preparations are pharmaceutically alternative if they contain the same number of one and the same active principle, but differ in the dosage form (for example, tablets and capsules) and / or by chemical form (various salts, ethers). Pharmaceutically alternative preparations are intended for one way of administration. In determining pharmaceutically alternative drugs, about the same approach and FDA.
It is necessary to pay attention to that until now in the literature, on the Internet, in oral speech you can find a fairly free use of the terms "synonyms of drugs", "analogues of drugs", "drug substitutes", etc. We want to warn specialists from using this terminology without a clear designation of the context corresponding to the above approaches.
For example, the term "synonyms of the HP" incorrectly continue to use in relation to generics. It would be even justified to some extent if there were no problem of therapeutic equivalence, interchangeability. Therefore, synonyms cannot be different trading names of drugs. But for substances, this may be, for example: Sodium metamizole as an international non-proprietary name (MNN) and analgin as a domestic pharmacopoeial name, paracetamol as a MNN and acetaminophen as a name adopted in the United States (USAN).
Bioequivalence generics
The same active ingredient, dosage, dosage form and the path of administration "bring together" drugs from different manufacturers, but this does not mean that the effectiveness of generics will also be equivalent, because The difference in the quality parameters of the active substance (for example, a polymorphism), as part of auxiliary substances and / or production process, can lead to differences in the effectiveness of these drugs. This fact has long been known and discussed from the middle of the last century.
As a small departure, we note that the issue of influence of impurities on the effectiveness and safety of generics is quite often discussed. On this occasion, it can be said that subject to the requirements of the purity laid into a single state pharmacopoeial standard of Quality LS, the question of the influence of impurities in the general case is removed. Another thing is when such a quality standard (ie, the state pharmacopoeia) is in full form actually no, and the existing regulatory documentation of manufacturers (FSP and ND) is very diverse. In this case, the question of impurities in the same way as other parameters of quality remains open, which has an indirect effect on the efficiency and safety of drugs.
So, in connection with the heterogeneity of generics, the concept of biological equivalence arose. According to WHO documents, two drugs are bioequivalent if they are pharmaceutically equivalent or are pharmaceutically alternative, and their bioavailability from the point of view of the maximum concentration in blood plasma (Cmax), the time to achieve this concentration (Tmax) and the area under the pharmacokinetic curve (AUC) after Applications in the same molar dose under the same conditions are similar to that in which their effects are essentially the same. Approximately the same approach from the European Medicine Agency (EMA, www.ema.europa.eu) and FDA.
WHO and FDA recommend defining bioequivalence using the following tests in vivo and in vitro:
- comparative pharmacokinetic tests in humans (study of the concentration profile of drugs or its metabolites in biological fluids);
- comparative pharmacodynamic tests in humans (study of the effects caused by drugs);
- comparative clinical trials;
- Comparative studies in vitro (for example, Test "Dissolution").
The word "comparative" means that all of the above studies are carried out by comparing the corresponding parameters for the test drug and the drug comparison.
WHO publishes recommendations for choosing a comparison drug for vital LS. These recommendations include, in particular, for each MNN trade name of the original drug, which is recommended to be used as a preparation comparison when setting the interchangeability of generics. At the same time, appropriate dosage forms and dosages are also given.
In the US, the choice of comparison drug is carried out on the basis of data presented in the so-called Orange Book, which we will speak below. It also gives an indication of a specific drug in a certain dosage form, a specific dosage and a particular manufacturer. Preparations that can be used to compare with generics have a mark in the appropriate graph. There is also domestic documentation, which provides guidance on pharmacokinetic studies and dissolution tests to evaluate 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 interchangeable. Indeed, according to the definition of WHO, a interchangeable drug is a drug that is a therapeutically equivalent when comparing with a comparison preparation and which the drug comparison can be replaced in clinical practice. The same position is reflected in the documents of the FDA.
We will also adhere to an approach in which therapeutically equivalent drugs will be interchangeable. It remains only to solve the question: what drugs are considered therapeutically equivalent?
Criteria of therapeutic equivalence
Let's start with the determination of WHO: "Two drugs are therapeutically equivalent if they are pharmaceutically equivalent or are pharmaceutically alternative and after their use in one molar dose, their effectiveness and security are essentially the same when they are used in one way under the conditions described in the instructions" .
Now we present the definition of therapeutic equivalence, which is given by the FDA: "Medicinal preparations 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, in contrast to 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 one dose will not be therapeutically equivalent. Moreover, FDA after a general definition quite specifically describes all the conditions of therapeutic equivalence.
1. Medicinal preparations must be allowed to use as efficient and safe.
2. Preparations should be pharmaceutically equivalent.
3. Preparations should be bioequivalent, i.e. Conditions must be observed:
- For them, existing or there are no potential problems with bioequivalence, and they meet the requirements of the relevant standard when conducting in vitro tests or
- For them, there are existing or potential problems with bioequivalence, but it has been shown that they comply with the requirements of the appropriate standard of bioequivalence.
4. Preparations must have proper instructions.
5. Preparations should be made in accordance with the requirements of appropriate production practice (i.e. GMP).
The FDA publishes an important document having the official name "APPROVED DRUG Products with Therapeutic Equivalence Evaluations", which can be translated about as "drugs allowed to use their therapeutic equivalence." Briefly this document is customary called the Orange Book.
Actually, the above approaches to the assessment of the therapeutic equivalence of drugs of specific manufacturers and reflected FDA in this edition. FDA specialists indicate that the use of relevant therapeutic equivalence codes can serve as a reference when replacing one drug to another and help, in particular, in reducing the cost of treatment. It is also necessary to remember that the basic value of the Orange Book of the FDA is that it has an electronic version, and the updated daily.
It should be noted that at present, the situation in domestic terminology there was a situation where the test of bioequivalence means only the study of the concentration profile of the drug substance, i.e. Pharmacokinetic studies. And domestic specialists believe that it is impossible to identify bioequivalence and therapeutic equivalence, since the latter can only be confirmed by carrying out full-fledged clinical studies on the protocol. The overall documentation implies either directly indicates the identity of these concepts. Therefore, in the Orange Book of the FDA, a marker about therapeutic equivalence can be put on the basis of a positive result in the study of bioequivalence pharmacokinetic approach. Self-sufficiency of such studies in most cases is due to the fact that the concentration profile of the drug in the blood plasma corresponds to this in the place of action.
Some therapeutic equivalence criteria used by the FDA, we will also discuss below. But in general, we believe that the FDA approach to solving the problem of interchangeability of drugs is quite reasonable and most worked. But with the obligatory implementation of all the above conditions. We emphasize that the therapeutic equivalence codes can serve as a guide in the "Efficiency" and "Security" directions, if the problem is solved in the direction of "quality".
Therapeutic equivalence and GMP
By establishing the therapeutic equivalence criteria (i.e. interchangeability) of drugs, FDA indicates the need to match their production with GMP requirements. This is definitely very important. Indeed, if the LANs are not produced according to GMP standards, they cannot be homogeneous from the series to the series. And it affects all the parameters of the drug: on quality, efficiency and safety. Therefore, proven therapeutic equivalence for one series of such products will not mean that all products subsequently will meet the necessary bioequivalence standards.
It should be understood that the state quality control does not solve the problem as a whole, even if it would be possible to do for all manufactured and imported LS. Therefore, currently around the world and in our country we are talking about the shift of the accent from the quality control of the LAN to ensure quality. Earlier, we have repeatedly indicated that the manufacturer at the exit has high-quality medicines when they are obtained as such in the production process, and not because it is well rejected by poor-quality. Following this principle entails the full compliance of the enterprise with the requirements of GMP (and even more), the introduction of an institution of authorized persons, attracting exclusively qualified personnel, reducing the acute deficit of specialists (technologists, analysts, etc.) and much more.
Here we will also add that the manufacturer's own resources in the field of scientific research and development play a large role in providing the quality of LS. And than these resources are more developed and more closely interacting with the divisions of production, control and quality assurance, the greater the extent can be confident as appropriate products.
Equivalence without research
The initial position is such that if the LS is intended for systemic use (the drug substance is determined in systemic bloodstream), then pharmacokinetic bioequivalence studies are necessary. If the effect of the drug is not due to the appearance of the active substance in the systemic bloodstream or it is difficult to determine there is difficult to existing analytical methods, then pharmacodynamic or even full-fledged clinical studies are necessary.
But there is a question of comparison, for example, injection facilities. If these are ready-made solutions that are pharmaceutically equivalent preparations and intended for intravenous administration, how to establish their therapeutic equivalence and is it necessary to do this?
According to WHO, LS reproduced can be considered therapeutically equivalent without additional studies in the following cases.
1. Medicinal preparations 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 identical concentrations. Certain excipients (for example, creating a buffer environment, as well as preservatives and antioxidants) may differ in the following condition: if it can be demonstrated that this does not affect the safety and / or efficacy of the drug.
2. Medicinal preparations are solutions for oral administration (for example, syrups, elixirs, tincture) containing the same active ingredient in the same molar concentration and, in essentially, the same auxiliary substances in comparable concentrations. At the same time, close attention should be paid to the consideration of those auxiliary substances that affect the absorption and stability of the active substance in the gastrointestinal tract.
3. Medicinal preparations are powders for the preparation of solutions, and the resulting solutions must comply with the criteria specified in paragraphs 1 or 2.
4. Medicinal preparations are gases.
5. Ear and eye medicines that are aqueous solutions and containing the same active substance (substances) in the same molar concentration and, in essentially, the same excipients in comparable concentrations. Certain excipients (for example, preservatives, substances that create a buffer medium, corrective osmotic properties and viscosity) may differ from their use should not affect the safety and / or efficacy of the drug.
6. Medicinal preparations for local use, which are aqueous solutions and containing the same active substance (substance) in the same molar concentration and, essentially, the same auxiliaries in comparable concentrations.
7. Medicinal preparations that are aqueous solutions for use in the form of inhalations in a nebulizer or as nasal sprays intended for use using essentially identical devices and containing the same active substance (substances) in the same concentration and , in essence, the same auxiliary substances in comparable concentrations. Medicinal preparations may contain different auxiliary substances, provided that their use should not affect safety and / or efficiency of drugs.
Thus, the above situations remove the need for relevant research. And the lack of influence differing in the composition of the auxiliary substances in these cases, it is obviously should demonstrate by providing additional information. In general, it is necessary to understand that the guarantee of therapeutic equivalence of the drug in the described cases will be the compliance of its quality with the requirements of regulatory documentation.
Separate problems requiring attention
When using drugs, with their purchase under government contracts, I would like to have a clear guide in which it would be written out which drugs are interchangeable. Such leadership could be an analogue of the Orange Book. But when it is formed, and when establishing the relevant rules, a mass of specific points is to be taken into account, except the above-described general rules. Let us dwell on some private problems.
Mnn. It is known that the placement of the order for the supply of drugs should be carried out in the MNN. The exception is insulins and cyclosporin, for which this can be done in the trade names. But it should be noted that the MNN (or another name, if NMN is missing) can not serve as the only guide.
First, drugs with one active substance (MNN) may differ in other characteristics (dosage, dosage form, method of use), which generally eliminates their interchangeability.
Secondly, with a formal approach, there is a chance to make a mistake, since WHO assigns MNN (and it is taken into account in the State Register of the Russian Federation) usually for acids and grounds (if any). For salts, ethers and other derivatives from the main structure of the INN, can be assigned only if such derivatives are the only possible option. For example, a nnn is assigned to salt - sodium metamizole. And it is done for the reason that in the form of acid metamizole does not exist due to instability, but this is a rare case. When making a decision, an error may be that for one MNN really can actually exist different active substances, for example: ciprofloxacin (in the form of a base) and ciprofloxacin hydrochloride (salt), hydrocortisone (main structure) and hydrocortisone acetate (ester - a derivative of basic structures). As we indicated above, preparations containing different salts and ethers are pharmaceutically alternative. FDA specialists such drugs are not considered therapeutically equivalent, and with this it is necessary to agree, because in general, the chemical modifications of the active substances pursue the objectives of changing solubility, stability, crystallinity, particle size, bioavailability, etc., which ultimately affects safety and the effectiveness of the drug.
Replacement of the dosage form. A radical dosage change can give a negative effect at all. For example, LS for parenteral and oral administration is not equivalent and not interchangeable. Moreover, the patient can be unconscious, and it requires injections. A drug may be required for rectal administration due to the fact that the patient cannot swallow. Preparations for local and systemic use, even if they are used to treat one pathology, have completely different efficacy (systemic efficient).
It is known that LS, having different ways of administration, can generally be applied in different testimony. The housing example is phenoterol. Preparation of Berotek, solution or aerosol for inhalations - bronchilation agent (for example, to relocate bronchial asthma attacks), and PARTYSISEN, Tablets or concentrate for infusion - tocolic (preventing premature genera).
It also needs to be noted that the number of dosage units in the package may also matter. For example, contraceptive pills. In one pack - 21 tablets. In another - 28 tablets, of which 7 are placebo. FDAs such drugs do not consider therapeutic equivalents.
Pharmaceutically alternative preparations are powders for injections to be dissolved, concentrated solutions for injections to be diluted, and ready-made solutions for injections that do not require similar preliminary manipulations. Such drugs according to FDA are also not therapeutically equivalent.
Combined drugs. The problem is to replace the combined drug on monopreparations containing the same active substances and in the same dosages as in combination. For example, in the "review of the practice of consideration of complaints against actions (inaction) of the Customer, an authorized body, a specialized organization, auction commission in the field of health care in accordance with the provisions of the Federal Law of July 21, 2005 No. 94-FZ" (prepared by controlling Placing a state order of FAS Russia, July 2011) It is indicated that "with the procedure for the formation of the customer of lots for the purchase of anti-virus drugs: combined and monopreparations intended for the treatment of persons infected by the human immunodeficiency virus, it is necessary to take into account that combined and monopreparations in the same combination In the form of 2 or 3 tablets are interchangeable. " If we accept that it is permissible, the solution to this problem must be specific, i.e. Adopted for each drug based on scientific data, taking into account the above-mentioned criteria for therapeutic equivalence.
Dura Lex ...
The activities associated with drugs are regulated by law. This applies incl. and procurement of LS in government contracts. For example, according to the Federal Law No. 94-FZ (part 3.1 of Art. 34), "the auction documentation cannot contain an indication of service signs, branded names, patents, useful models, industrial samples, the name of the place of origin of the goods or the name of the manufacturer, and Also, the requirements for the product, information, work, services, if such requirements entail a limit on the number of participants in the placement of the order. "
But, according to the specialists of the Garant company, "at the same time it must be remembered that the purpose of placing the order is to meet the needs of the customer (Article 3 of Law No. 94-FZ). As the courts noted in this regard, depending on their needs, the Customer must establish specific requirements for quality, to the functional characteristics (consumer properties) of the goods, to the size, packaging, i.e. The needs of the customer are a decisive factor in establishing them of relevant requirements (Resolution of the FAS of the West Siberian District of September 7, 2010 in case No.A03-2442 / 2010). " And the question of the legitimacy of the specification of specific drug requirements, in our opinion, should be decided taking into account the medical aspects that are discussed above.
Known, for example, the situation prevailing in 2010 when purchasing a zoldronic acid preparation. When placing an order, the Ministry of Defense of the Russian Federation concretized the dosage form and the concentration of the drug in such a way that this actually indicated the preparation of a particular manufacturer - a solution for infusion infusion 5 mg / 100 ml is released only called Aklast and produced by NOVartis. In this case, the FAS was decided to violate, which limits the number of participants in orders, and the customer was issued a corresponding prescription. The decision of the FAS was appealed to the Ministry of Defense in the arbitration court of two instances, but left in force. The objections from the manufacturer of drugs in this case did not come, i.e. He agreed that the lyophilisate or concentrate for the preparation of the solution for infusions, which are also available on the market, in this case will be equivalent to the substitute for the finished solution, although, according to the requirements of the FDA, this is not the case.
But the other seemingly similar to the situation in which the other decision was made. In 2010, the Kurgan Regional Clinical Hospital has placed an order for the purchase of a drug containing docetaxel. At the same time, additional requirements were included in the auction documentation: 1) a concentrate for the preparation of a solution for infusions 20 mg, the volume of filling the vial of 24.4 mg / 0.61 ml in a set with a solvent of 1.98 ml in a bottle No. 1; 2) Concentrate for the preparation of a solution for infusion 80 mg, the volume of filling the vial of 94.4 mg / 2.36 ml in a set with a solvent of 7.33 ml in a bottle No. 1. Such detailing, in fact, again pointed to a specific drug - Taxother. Moreover, the Customer did not hide this: according to the law No. 94-FZ, in the auction documentation he indicated not only the MNN, but also a trade name with the compulsory words "or equivalent". FAS Still, a violation was discussed, since the equivalent with such a form of release is actually no on the market, but there are other drugs that could be replaced. However, when considering the case in the Arbitration Court, the FAS decision was invalid.
A completely unexpected turn, which even a specialist, at first glance, seems strange. But the scientific rationale for which the court focused was the following. Quote: "... The challenged decision of FAS in the Kurgan region is illegal due to the following: the interested person is not taken into account that the requirement specified in the documentation on the auction requires the volume of filling of the bottle - 24.4 mg / 0.61 ml and 94.4 mg / 2 , 36 ml is the only possible content to ensure the effective use of the drug required by the Customer, which believes that this filling provides adequate dosage taking into account the adhesion (sedimentation on the vessel walls) of the drug and allows you to compensate for the loss of fluid when preparing a pre-mixed solution, believes that The excess of the drug in the bottle ensures after dilution its contents of the desired dose of 20 mg, indicated on the bottle label. A different filling of the bottle as a result of adhesion will lead to a real dosage, which will be lower below, as a result, it will not be possible when applying the therapeutic effect.
The same concentrates the concentrate for the preparation of infusions of 80 mg. It insists that only the volume of filling the bottle supplied by the applicant and indicated in the documentation on the auction (24.4 mg / 0.61 ml and 94.4 mg / 2.36 ml), allows for accurate dosage without additional measurements, while The other volume bottle creates a significant risk of erroneous dosage. Thus, the indication in the auction documentation on the volume of filling the bottle actually was to ensure the supply of the drug in the form in which it is possible to ensure its effective use in the treatment of patients with cancer diseases, this circumstance was not taken into account by UFAS in the Kurgan region when making a contested decision . ".
The examples of the examples once again indicate that even if there are some general landmarks, each specific case requires separate consideration. A certain analogue of an orange book can be brought to solving this problem, in which it can be indicated that one drug has no interchangeable drugs, and the other has. But at the same time it should be understood that this is a huge job. In fact, this is a scientific work based on evidence.
Conclusion
When considering the issues of impressibility of drugs, the LS should proceed from the fact that the reproduced LS containing the same active drug substance are not therapeutically equivalent, and therefore are not interchangeable. Their therapeutic equivalence must be proved for each drug of each manufacturer. These evidence should be based on scientifically based data, and the adoption of a specific decision on the drug replacement should be due to medical specificity and can be based on the information presented in the relevant manual.
Once again, pay attention to the fact that with an unresolved question regarding the quality of drugs produced, incl. With regard to state pharmacopoeia, making decisions related to interchangeability of drugs remains difficult.
Literature
1. Biological accessibility of medicines: principles and problems. Dokl. Scientific WHO groups №536. - Geneva: WHO, 1975.
2. Garant Expert: Garant maximum (electronic resource).
3. Evaluation of drug bioequivalence. 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 of October 31, 2007 No. 16811-UP / D04, 8035-Sun and / IA / 20555.
5. Tensetova A.I., Azhgikhin I.S. Dosage form and therapeutic efficacy of drugs. - M.: Medicine, 1974. - 336 p.
6. Federal Law No. 61-FZ dated April 12, 2010 "On the circulation of medicines".
7. Federal Law No. 94-FZ dated July 21, 2005 "On the placement of orders for the supply of goods, work, the provision of services for state and municipal needs."
8. Colds 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 Council of 6 November 2001 on the Community Code Relating to Medicinal Products for Human Use.
12. Generic prescripting 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 Registry of Pharmaceuticals for Human Use: Quality M4Q (R1). - Geneva: Ich, 2002.
14. ICH HARMONIED TRIPARTITE GUIDELINE: The Common Technical Document for the Registry of Pharmaceuticals for Human Use: Safety. M4S (R2). - Geneva: Ich, 2002.
15. Ich Harmonized TripArtite Guideline: The Common Technical Document for the Registry of Pharmaceuticals for Human Use: Efficacy. M4E (R1). - Geneva: Ich, 2002.
16. Joint Statement Between The International Pharmaceutical 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.
Often the term "Generic" is incorrectly replaced by the term "equivalent medicinal substance". Actually, a similar term is inseminious, since there is no concept of "equivalence of medicinal substances". The following equivalence types are distinguished: pharmaceutical, biological and therapeutic. In the countries of the European Union and in the United States uses the definitions of the pharmaceutical equivalence of medicinal substances.
Medicinal preparations 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 (Emea, The Rules Governing Medicinal Products in the European Union Investigation of Bioavailability and Bioquivalence, v. 3c, 1998, pp. 231-244).
Pharmaceutically equivalent drugs contain the same active ingredients in the same dosage form, designed for one method of administration and identical to the strength of the action or concentration of active substances (FDA, Electronic Orange Book. Approved Drug Products with Therapeutic Equivalence Evaluations, 20th Edition, 2000).
The same ingredients determines the pharmaceutical equivalence of drugs, to assess their biological equivalence it is necessary to compare the peculiarities of the suction and distribution of drugs in the human body. The World Health Organization offers the following wording: "Two drugs are considered bioequivalent if they are pharmaceutically equivalent, have the same bioavailability and when appointing in the same dose ensure proper efficacy and safety."
Bioequivalence is adopted in Europe and in the United States.
Two drugs are bioequivalent if they are pharmaceutically equivalent or alternative and if their bio-sauna (speed and suction rate) after administration in the same molar dose is similar to that of their effectiveness and security are mostly the same (Emea, The Rules Governing Medicinal Products In The EUROPEAN UNION. INVESTIGATION OF BIOVAILABILITY AND BIOEQUIVALENCE, V.3C, 1998, PP. 231-244).
Bioequivalent drugs are pharmaceutically equivalent or pharmaceutically alternative drugs that have comparable bioavatomy in the study in similar experimental conditions (FDA, Electronic Orange Book, Approved Drug Products with therapeutic Equivalence Evaluations, 20th Edition, 2000).
Thus, the equivalence assessment of drugs is reduced not only to the evaluation of the identity of molecules - the existing principles of medicinal substances. The requirements for drugs in confirmation of their equivalence affect such aspects as control quality control (compliance with GMP standards), for instructions for drugs, labeled, etc.
The equivalence of drugs is also assessed by the physicochemical properties of active ingredients (degree of dispersion, polymorphism, etc.), the properties of auxiliary substances, the characteristics of the technological process, storage conditions, packaging (glass, plastic, paper, etc.).
1. Generic bioequivalence should be determined relative to the original drug. If it is not submitted in the national market, it takes it from the above-mentioned (primary market), where, according to the manufacturer's company, it most of all meets the requirements for quality, safety, efficiency and labeling.
2. If it is impossible to use the original drug with a standard, a drug may serve as a drug leading in the market, if its quality, safety and efficiency is confirmed.
3. In the absence of drug-leader, the recorded generic is produced in accordance with local, state or regional standards, including the International Pharmacopoeia and WHO management on registration requirements for determining the interchangeability of drugs produced by several manufacturers (Worldhealth Organization, 1996, Who Expert Expert CommitteeTee ON SPECIFICATIONS FOR PHARMACEUTICAL PREPARATIONS: THIRTY-FOURTH REPORT. WHO TECHNICAL REPORT SERIES No. 863, GENEVA, PP. 114-154).
The question naturally arises whether the species described are sufficiently described in order to believe that generic drugs and originals are the same in the therapeutic plan, that is, therapeutically equivalent.
According to European and American definitions, therapeutic equivalence provides, in addition to a similar pharmacokinetic profile, a similar estimate of the pharmacodynamic (therapeutic) effect.
The drug is a therapeutically equivalent to another drug if it contains the same active substance or medicinal substance and, according to the results of clinical studies, has the same efficacy and safety as the drug comparison, whose efficiency and security are installed (The Rules Governing Medicinal Products in the European UNION. INVESTIGATION OF BIOVAILABILITY AND BIOEQUIVALENCE, V. 3C, 1998, PP. 231-244).
Therapeutically equivalent drugs can only be considered if they are pharmaceutically equivalent and we can expect that they will have the same clinical effect and the same safety profile when using patients according to label guidelines (FDA, Electronic Orange Book. Approved Drug Products With WITH Therapeutic Equivalence Evaluations, 20th Edition, 2000).
Unlike bioequivalence, the definition of which is regulated by strict standards and does not cause as a rule, as a rule, in the interpretation of results, the absence of clear definitions of therapeutic equivalence leads to the uncertainty of both doctors and patients in the correctness of the choice of certain drugs of the generic series.
In the draft rules for evaluating the therapeutic equivalence of generics published in 1998, the project is proposed to indicate the presence or absence of therapeutic equivalence, as well as the drug with which a comparison was made (as a rule, this is the original drug).
Currently, when choosing a generic drug, it can be guided by the fact that the bioequivalence of medicinal substances is indirectly confirming their therapeutic efficacy.
Complete confidence in the similar efficacy of the preparations of one generic line can only be after comparative tests on therapeutic equivalence, the data will fully benefit the economic advantages of the wide use of generics. Currently, tests for therapeutic equivalence becomes mandatory in deriving new generic drugs to the market.