Stages of development of new drugs. Ways to create a new drug
The development of new drugs includes a series of successive stages.
First stage aimed at search for promising compounds possibly having a medicinal effect. The main routes are outlined above.
Second phase- This preclinical study of biological activity substances designated for further investigation. Preclinical study of a substance is divided into: pharmacological and toxicological.
Target pharmacological research- determination of not only the therapeutic efficacy of the drug and its effect on the body systems, but also possible adverse reactions associated with pharmacological activity.
At toxicological studies establish the nature and possible damaging effects on the body of experimental animals. Allocate three stages toxicological studies: 1) study of the toxicity of the drug with a single injection; 2) determination of chronic toxicity of a substance upon repeated administration for 1 year or more; 3) establishing the specific effect of the compound (oncogenicity, mutagenicity, effects on the fetus, etc.).
The third stage - clinical trials new medicinal substance. Held assessment of therapeutic or prophylactic efficacy, tolerability, establishing doses and regimens for the use of the drug, as well as comparative characteristics with other drugs. During clinical trials, four phase.
IN phase I determine the tolerability and therapeutic effect of the study drug on limited number of patients (5-10 people), as well as in healthy volunteers.
IN phase II clinical trials are carried out on a group of patients (100-200 people), as well as in the control group. To obtain reliable data, use "double blind" method when neither the patient nor the doctor, but only the head of the trial, knows which drug is being used. Efficacy and tolerability of a new pharmacological drug compared with those of a placebo or a drug of similar action.
aim phase III testing is to obtain additional information about the study pharmacological agent. At the same time, research is being carried out on hundreds or even thousands of patients in both inpatient and outpatient settings. After comprehensive clinical trials, the Pharmacological Committee gives a recommendation for practical use.
Phase IV research studies the effect of a medicinal product in practice in a variety of situations, with particular attention to the collection and analysis of data on the side effects of investigational medicinal products.
Viewed: 12173 | Added: 24 March 2013Sources of medicines can be:
- Products of chemical synthesis. Currently, most drugs are obtained in this way. There are several ways to find drugs among the products of chemical synthesis:
- pharmacological screening. toscreen- sift). A method of searching for substances with a certain type of pharmacological activity among a variety of chemical compounds synthesized by chemists on a special order. For the first time, pharmacological screening was used by the German scientist Domagk, who worked in the chemical concern IG-FI and searched for antimicrobial agents among compounds synthesized for dyeing fabrics. One of these dyes, red streptocide, was found to have an antimicrobial effect. This is how sulfa drugs were discovered. Screening is an extremely time-consuming and costly process: to detect a single drug, a researcher has to test several hundred or thousands of compounds. So, Paul Ehrlich, in the search for antisyphilitic drugs, studied about 1000 organic compounds of arsenic and bismuth, and only the 606th drug, salvarsan, turned out to be quite effective. Currently, for screening it is necessary to synthesize at least 10,000 parent compounds in order to believe with a greater degree of confidence that there is one (!) Potentially effective drug among them.
- Molecular design of drugs. The creation of scanning tomography and X-ray diffraction analysis, the development of computer technologies made it possible to obtain three-dimensional images of the active centers of receptors and enzymes and select molecules for them, the configuration of which exactly corresponds to their shape. Molecular engineering does not require the synthesis of thousands of compounds and their testing. The researcher immediately creates several molecules ideally suited to the biological substrate. However, in terms of its economic cost, this method is not inferior to screening. Neuraminidase inhibitors, a new group of antiviral drugs, were obtained by the method of molecular design.
- Reproduction of nutrients. Thus, mediator agents were obtained - adrenaline, norepinephrine, prostaglandins; agents with the activity of pituitary hormones (oxytocin, vasopressin), thyroid gland, adrenal glands.
- Targeted modification of molecules with already known activity. For example, it was found that the introduction of fluorine atoms into drug molecules, as a rule, increases their activity. By fluorination of cortisol, powerful glucocorticoid preparations were created; by fluorination of quinolones, the most active antimicrobial agents, fluoroquinolones, were obtained.
- Synthesis of pharmacologically active metabolites. When studying the metabolism of the tranquilizer diazepam, it was found that in the liver a substance with tranquilizing activity, oxazepam, is formed from it. Currently, oxazepam is synthesized and produced as a separate drug.
- Chance finds ("serendipity" method). The method got its name from Horace Walpole's tale "The Three Princesses of Serendipi". These sisters often made successful discoveries and found solutions to problems themselves without intentionally. An example of "serendipity" obtaining a drug is the creation of penicillin, which was largely due to the fact that A. Fleming accidentally drew attention to the fact that microorganisms had died in a moldy cup, forgotten in the thermostat at Christmas. Sometimes accidental discoveries are made as a result of a mistake. For example, mistakenly believing that the anticonvulsant effect of phenytoin is due to the fact that it is a folic acid antagonist, Glaxo Wellcome employees synthesized lamotrigine, a new anticonvulsant. However, it turned out that, firstly, the action of phenytoin is not associated with folic acid, and secondly, lamotrigine itself does not interfere with folate metabolism.
- Components of vegetable raw materials. Many plants contain substances with useful pharmacological properties, and the discovery of more and more new compounds continues to this day. Widely known examples of drugs derived from medicinal plant materials are morphine isolated from the opium poppy ( Papaversomniferum), atropine derived from belladonna ( Atropabelladonna).
- Animal tissues. Some hormonal preparations are obtained from animal tissues - insulin from the tissues of the pancreas of pigs, estrogens from the urine of stallions, FSH from the urine of women.
- The products of vital activity of microorganisms. A number of antibiotics, drugs for the treatment of atherosclerosis from the group of statins are obtained from the culture fluid of various fungi and bacteria.
- Mineral raw materials. Petroleum jelly is obtained from the by-products of oil refining, which is used as an ointment base.
Each drug, before being used in practical medicine, must undergo a certain procedure of study and registration, which would guarantee, on the one hand, the effectiveness of the drug in the treatment of this pathology, and, on the other hand, its safety. The introduction of medicines is divided into a number of stages (see table 1).
Scheme 2 shows the main stages of drug movement in the process of its development and study. After the completion of phase III clinical trials, the documentation is again submitted to the Pharmacological Committee (the volume of a complete dossier can be up to 1 million pages) and is registered in the State Register of Medicines and Medical Devices within 1-2 years. Only after that, the pharmacological concern has the right to start industrial production of the medicinal product and its distribution through the pharmacy network.
Table 1. Brief description of the main stages in the development of new drugs.
| Stage | a brief description of |
| Preclinical trials (»4 years) After completion, the materials are submitted for examination to the Pharmacological Committee, which authorizes the conduct of clinical trials. |
|
| Clinical trials (» 8-9 years) Includes 3 phases. Examination of documentation by the Pharmacological Committee is carried out after the completion of each phase. The medicine can be withdrawn at any stage. |
|
Scheme 2. The main stages of research and introduction of the drug into medical practice.
However, in parallel with the sale of the drug, the pharmaceutical concern organizes Phase IV clinical trials (post-marketing studies). The purpose of this phase is to identify rare but potentially dangerous side effects of the drug. Participants in this phase are all practitioners who prescribe the drug and the patient who uses it. If serious deficiencies are found, the medicine may be withdrawn by the concern. For example, after the new third-generation fluoroquinolone grepafloxacin successfully passed all stages of testing and went on sale, the manufacturer recalled the drug in less than a year. In post-marketing studies, grepafloxacin has been found to be a cause of fatal arrhythmias.
When organizing and conducting clinical trials, the following requirements must be met:
- The study must be controlled - i.e. In parallel with the study drug group, a group should be recruited that receives a standard comparator drug (positive control) or an inactive drug that mimics the study drug in appearance (placebo control). This is necessary in order to eliminate the element of self-hypnosis in the treatment of this medicine. Depending on the type of control, there are:
- Simple blind study: the patient does not know whether he is taking a new drug or a control drug (placebo).
- Double-blind study: both the patient and the doctor who dispenses the drugs and evaluates their effect do not know whether the patient is receiving a new drug or a control drug. Only the head of the study has this information.
- Triple-blind study: neither the patient nor the physician and study director know which group is being treated with the new drug and which with the control agents. Information about this is with an independent observer.
- The study must be randomized - i.e. a homogeneous group of patients should be randomly divided into experimental and control groups.
- The study must be organized in compliance with all ethical norms and principles that are set out in the Declaration of Helsinki.
Sources of medicines can be:
Products of chemical synthesis. Currently, most drugs are obtained in this way. There are several ways to find drugs among the products of chemical synthesis:
pharmacological screening. to screen- sift). A method of searching for substances with a certain type of pharmacological activity among a variety of chemical compounds synthesized by chemists on a special order. For the first time, pharmacological screening was used by the German scientist Domagk, who worked in the chemical concern IG-FI and searched for antimicrobial agents among compounds synthesized for dyeing fabrics. One of these dyes, red streptocide, was found to have an antimicrobial effect. This is how sulfa drugs were discovered. Screening is an extremely time-consuming and costly process: to detect a single drug, a researcher has to test several hundred or thousands of compounds. So, Paul Ehrlich, in the search for antisyphilitic drugs, studied about 1000 organic compounds of arsenic and bismuth, and only the 606th drug, salvarsan, turned out to be quite effective. Currently, for screening it is necessary to synthesize at least 10,000 parent compounds in order to believe with a greater degree of confidence that there is one (!) Potentially effective drug among them.
Molecular design of drugs. The creation of scanning tomography and X-ray diffraction analysis, the development of computer technologies made it possible to obtain three-dimensional images of the active centers of receptors and enzymes and select molecules for them, the configuration of which exactly matches their shape. Molecular engineering does not require the synthesis of thousands of compounds and their testing. The researcher immediately creates several molecules ideally suited to the biological substrate. However, in terms of its economic cost, this method is not inferior to screening. Neuraminidase inhibitors, a new group of antiviral drugs, were obtained by the method of molecular design.
Reproduction of nutrients. Thus, mediator agents were obtained - adrenaline, norepinephrine, prostaglandins; agents with the activity of pituitary hormones (oxytocin, vasopressin), thyroid gland, adrenal glands.
Targeted modification of molecules with already known activity. For example, it was found that the introduction of fluorine atoms into drug molecules, as a rule, increases their activity. By fluorination of cortisol, powerful glucocorticoid preparations were created; by fluorination of quinolones, the most active antimicrobial agents, fluoroquinolones, were obtained.
Synthesis of pharmacologically active metabolites. When studying the metabolism of the tranquilizer diazepam, it was found that in the liver a substance with tranquilizing activity, oxazepam, is formed from it. Currently, oxazepam is synthesized and produced as a separate drug.
Chance finds ("serendipity" method). The method got its name from Horace Walpole's tale "The Three Princesses of Serendipi". These sisters often made successful discoveries and found solutions to problems themselves without intentionally. An example of "serendipity" obtaining a drug is the creation of penicillin, which was largely due to the fact that A. Fleming accidentally drew attention to the fact that microorganisms died in a moldy cup, forgotten in the thermostat at Christmas. Sometimes accidental discoveries are made as a result of a mistake. For example, mistakenly believing that the anticonvulsant effect of phenytoin is due to the fact that it is a folic acid antagonist, GlaxoWellcome employees synthesized lamotrigine, a new anticonvulsant. However, it turned out that, firstly, the action of phenytoin is not associated with folic acid, and secondly, lamotrigine itself does not interfere with folate metabolism.
Components of vegetable raw materials. Many plants contain substances with useful pharmacological properties, and the discovery of more and more new compounds continues to this day. Widely known examples of drugs derived from medicinal plant materials are morphine isolated from the opium poppy ( Papaver somniferum), atropine derived from belladonna ( Atropa belladonna).
Animal tissues. Some hormonal preparations are obtained from animal tissues - insulin from the tissues of the pancreas of pigs, estrogens from the urine of stallions, FSH from the urine of women.
The products of vital activity of microorganisms. A number of antibiotics, drugs for the treatment of atherosclerosis from the group of statins are obtained from the culture fluid of various fungi and bacteria.
Mineral raw materials. Petroleum jelly is obtained from the by-products of oil refining, which is used as an ointment base.
Each drug, before being used in practical medicine, must undergo a certain procedure of study and registration, which would guarantee, on the one hand, the effectiveness of the drug in the treatment of this pathology, and on the other hand, its safety. The introduction of medicines is divided into a number of stages (see table 1).
Scheme 2 shows the main stages of drug movement in the process of its development and study. After the completion of the III phase of clinical trials, the documentation is again submitted to the Pharmacological Committee (the volume of a complete dossier can be up to 1 million pages) and is registered in the State Register of Medicines and Medical Devices within 1-2 years. Only after that, the pharmacological concern has the right to start industrial production of the medicinal product and its distribution through the pharmacy network.
Table 1. Brief description of the main stages in the development of new drugs.
|
Stage |
a brief description of |
|
Preclinical trials (4 years) After completion, the materials are submitted for examination to the Pharmacological Committee, which authorizes the conduct of clinical trials. |
In vitro research and creation of a medicinal substance; Animal studies (at least 2 species, one of which is non-rodent). Research program: Pharmacological profile of the drug (mechanism of action, pharmacological effects and their selectivity); Acute and chronic drug toxicity; Teratogenic effect (non-inherited defects in offspring); Mutagenic action (inherited defects in offspring); Carcinogenic effect (tumor cell transformation). |
|
Clinical trials (8-9 years) Includes 3 phases. Examination of documentation by the Pharmacological Committee is carried out after the completion of each phase. The medicine can be withdrawn at any stage. |
PHASE I. IS THE SUBSTANCE SAFE? The pharmacokinetics and the dependence of the effect of the drug on its dose are studied in a small number (20-50 people) of healthy volunteers. PHASE II. DOES THE SUBSTANCE EFFECT IN THE PATIENT BODY? Perform on a limited number of patients (100-300 people). Determine the tolerability of therapeutic doses by a sick person and the expected undesirable effects. PHASE III. IS THE SUBSTANCE EFFECTIVE? Perform on a large number of patients (at least 1,000-5,000 people). The degree of severity of the effect is determined, undesirable effects are clarified. |
Scheme 2. The main stages of research and introduction of the drug into medical practice.
However, in parallel with the sale of the drug, the pharmaceutical concern organizes the IV phase of clinical trials (post-marketing studies). The purpose of this phase is to identify rare but potentially dangerous side effects of the drug. Participants in this phase are all practitioners who prescribe the drug and the patient who uses it. If serious deficiencies are found, the medicine may be withdrawn by the concern. For example, after the new third-generation fluoroquinolone grepafloxacin successfully passed all stages of testing and went on sale, the manufacturer recalled the drug in less than a year. In post-marketing studies, grepafloxacin has been found to be a cause of fatal arrhythmias.
When organizing and conducting clinical trials, the following requirements must be met:
The study must be controlled – i.e. In parallel with the study drug group, a group should be recruited that receives a standard comparator drug (positive control) or an inactive drug that mimics the study drug in appearance (placebo control). This is necessary in order to eliminate the element of self-hypnosis in the treatment of this medicine. Depending on the type of control, there are:
Simple blind study: the patient does not know whether he is taking a new drug or a control drug (placebo).
Double-blind study: both the patient and the doctor who dispenses the drugs and evaluates their effect do not know whether the patient is receiving a new drug or a control drug. Only the head of the study has this information.
Triple-blind study: neither the patient nor the physician and study director know which group is being treated with the new drug and which with the control agents. Information about this is with an independent observer.
The study must be randomized – i.e. a homogeneous group of patients should be randomly divided into experimental and control groups.
The study must be organized in compliance with all ethical norms and principles that are set out in the Declaration of Helsinki.
It is known that in the process of creating new drugs, as a rule, there are two main determining factors - objective and subjective. Each of these factors is important in its own way, but only if their force vectors are unidirectional, it is possible to achieve the ultimate goal of any pharmaceutical research - obtaining a new drug.
The subjective factor is determined primarily by the desire of the researcher to deal with a scientific problem, his erudition, qualifications and scientific experience. The objective side of the process is associated with the selection of priority and promising research areas that can affect the level of quality of life (i.e., the QoL index), as well as with commercial attractiveness.
A detailed examination of the subjective factor ultimately comes down to finding an answer to one of the most intriguing philosophical questions: what place was given to His Majesty the Case in that this particular researcher (or group of researchers) was at the right time and in the right place to be relevant to the development of a particular drug? One of the striking historical examples of the significance of this factor is the history of the discovery of antibiotics and lysozyme by A. Fleming. In this regard, the head of the laboratory in which Fleming worked wrote: “Despite all my respect for the father of English antibiotics, I must say that not a single self-respecting laboratory assistant, and even more so a bacteriologist, would never allow himself to have experiments on a Petri dish of such purity that mold could grow in it. And if we take into account the fact that the creation of penicillin took place in 1942, i.e. at the very height of the Second World War and, consequently, at the peak of infectious complications from gunshot wounds in hospitals, when mankind more than ever needed a highly effective antibacterial drug, the thought of providence involuntarily comes up.
As for the objective factor, its understanding is more amenable to logical cause-and-effect analysis. And this means that at the stage of developing a new drug, the criteria that determine the direction of scientific research come to the fore. The paramount factor in this process is an acute medical need or the opportunity to develop new or improve old treatments, which can ultimately affect the quality of life. A good example is the development of new effective anticancer, cardiovascular, hormonal drugs, and means of combating HIV infection. It will be time to remind that an indicator of the level of quality of life is the physical and emotional state of a person, intellectual activity, a sense of well-being and satisfaction with life, social activity and the degree of its satisfaction. It should be noted that the QoL index is directly related to the severity of the disease, which determines the financial costs of society for hospitalization, patient care, the cost of a course of therapy, and the treatment of chronic pathology.
The commercial attractiveness of the drug is due to the incidence of a particular pathology, its severity, the amount of treatment costs, the sample size of patients suffering from this disease, the duration of the course of therapy, the age of patients, etc. In addition, there are a number of nuances associated with the logistical and financial capabilities of the developer and the future manufacturer. This is determined by the fact that, firstly, the developer spends most of the funds allocated for scientific research on maintaining the won and strongest positions in the market (where he is already, as a rule, the leader); secondly, at the forefront of the development of a new drug is the ratio between the estimated costs and the real figures of the profit that the developer expects to receive from the sale of the drug, as well as the time ratio of these two parameters. So, if in 1976 pharmaceutical companies spent an average of about $54 million on research and release of a new drug, then already in 1998 - almost $597 million.
The process of developing and marketing a new drug takes an average of 12-15 years. The growth of costs for the development of new drugs is associated with the tightening of society's requirements for the quality and safety of pharmaceuticals. In addition, if we compare the costs of research and development in the pharmaceutical industry with other types of profitable business, in particular with radio electronics, it turns out that they are 2 times more, and in comparison with other industries - 6 times.
Methodology for the discovery of new drugs
In the recent past, the main method for discovering new drugs was an elementary empirical screening of existing or newly synthesized chemical compounds. Naturally, there can be no "pure" empirical screening in nature, since any study is ultimately based on previously accumulated factual, experimental and clinical material. A vivid historical example of such screening is the search for antisyphilitic drugs conducted by P. Ehrlich among 10 thousand arsenic compounds and ended with the creation of the drug salvarsan.
Modern high-tech approaches involve the use of the HTS method (High Through-put Screening), i.e. method of empirical design of a new highly effective drug compound. At the first stage, using high-speed computer technology, hundreds of thousands of substances are tested for activity relative to the molecule under study (most often this means the molecular structure of the receptor). At the second stage, the structural activity is directly modeled using special programs such as QSAR (Quantitative Structure Activity Relationship). The end result of this process is the creation of a substance with the highest level of activity with minimal side effects and material costs. Modeling can proceed in two directions. The first is the construction of an ideal "key" (i.e. mediator), suitable for a natural natural "lock" (i.e. receptor). The second is the construction of a "lock" under the existing natural "key". The scientific approaches used for these purposes are based on a variety of technologies, ranging from molecular genetics and NMR methods to direct computer simulation of the active molecule in three-dimensional space using CAD (Computer Assisted Design) programs. However, in the end, the process of designing and synthesizing potential biologically active substances is still based on the intuition and experience of the researcher.
As soon as a promising chemical compound is synthesized, and its structure and properties are established, proceed to preclinical stage animal testing. It includes a description of the process of chemical synthesis (data on the structure and purity of the drug are given), experimental pharmacology (i.e. pharmacodynamics), the study of pharmacokinetics, metabolism and toxicity.
Let's highlight the main priorities of the preclinical stage. For pharmacodynamics is a study of the specific pharmacological activity of the drug and its metabolites (including the determination of the rate, duration, reversibility and dose-dependence of effects in model experiments in vivo, ligand-receptor interactions, influence on the main physiological systems: nervous, musculoskeletal, genitourinary and cardiovascular); For pharmacokinetics And metabolism- this is the study of absorption, distribution, protein binding, biotransformation and excretion (including calculations of the rate constants of elimination (Kel), absorption (Ka), excretion (Kex), drug clearance, area under the concentration-time curve, etc.); For toxicology- this is the definition of acute and chronic toxicity (at least in two types of experimental animals), carcinogenicity, mutagenicity, teratogenicity.
Experience shows that during testing, about half of the candidate substances are rejected precisely because of low stability, high mutagenicity, teratogenicity, etc. Preclinical studies, as well as clinical studies, can be conditionally divided into four phases (stages):
Preclinical studies (I stage) (Selection of promising substances)
1.Assessing patent opportunities and applying for a patent.
2.Basic pharmacological and biochemical screening.
3.Analytical study of the active substance.
4.Toxicological studies to determine the maximum tolerated doses.
Preclinical studies (stage II) (Pharmacodynamics/kinetics in animals)
1.Detailed pharmacological studies (main effect, adverse reactions, duration of action).
2.Pharmacokinetics (absorption, distribution, metabolism, excretion).
Preclinical studies (Stage III) (Safety rating)
1.Acute toxicity (single administration to two animal species).
2.Chronic toxicity (repeated administration to two animal species).
3.Toxicity study on the effect on the reproductive system (fertility, teratogenicity, peri- and postnatal toxicity).
4.Mutagenicity study.
5.Impact on the immune system.
6.Skin-allergic reactions.
Preclinical studies (stage IV) (Early technical development)
1.Synthesis under production conditions.
2.Development of analytical methods to determine the drug, degradation products and possible contamination.
3.Synthesis of a drug labeled with radioactive isotopes for pharmacokinetic analysis.
4.Stability study.
5.Production of dosage forms for clinical trials.
After evidence of the safety and therapeutic efficacy of the drug, as well as the possibility of quality control, is obtained on the basis of the necessary preclinical studies, the developers draw up and send an application to the authorizing and regulatory authorities for the right to conduct clinical trials. In any case, before the developer receives permission to conduct clinical trials, he must submit to the licensing authorities an application containing the following information: 1) data on the chemical composition of the medicinal product; 2) a report on the results of preclinical studies; 3) procedures for obtaining the substance and quality control in production; 4) any other available information (including clinical data from other countries, if available); 5) description of the program (protocol) of the proposed clinical trials.
Thus, human trials can only be started if the following basic requirements are met: information from preclinical trials convincingly shows that the drug can be used in the treatment of this particular pathology; the clinical trial plan is adequately designed and, therefore, clinical trials can provide reliable information about the efficacy and safety of the drug; the drug is safe enough to be tested in humans and subjects will not be exposed to undue risk.
Schematically, the transitional stage from preclinical to clinical studies can be represented as follows:
The program of clinical trials of a new drug in humans consists of four phases. The first three are carried out before the registration of the drug, and the fourth, which is called post-registration, or post-marketing, is carried out after the drug is registered and approved for use.
1st phase of clinical trials. Often this phase is also called biomedical, or clinical pharmacological, which more adequately reflects its goals and objectives: to establish the tolerability and pharmacokinetic characteristics of the drug in humans. As a rule, healthy volunteers in the amount of 80 to 100 people take part in the 1st phase of clinical trials (CT) (usually 10-15 young healthy men in our conditions). The exception is trials of anticancer drugs and AIDS drugs because of their high toxicity (in these cases, trials are immediately carried out on patients with these diseases). It should be noted that, on average, about 1/3 of the candidate substances are screened out in the 1st phase of CI. In fact, Phase 1 CT should answer the main question: is it worth continuing to work on a new drug, and if so, what will be the preferred therapeutic doses and routes of administration?
Phase 2 clinical trials - the first experience of using a new drug for the treatment of a specific pathology. This phase is often referred to as pilot or sighting studies because the results obtained from these trials allow planning for more expensive and extensive studies. The 2nd phase includes both men and women in the amount of 200 to 600 people (including women of childbearing age, if they are protected from pregnancy and control pregnancy tests have been carried out). Conventionally, this phase is divided into 2a and 2b. At the first stage of the phase, the problem of determining the level of drug safety in selected groups of patients with a specific disease or syndrome that needs to be treated is solved, while at the second stage, the optimal dose level of the drug is selected for the subsequent, 3rd phase. Naturally, phase 2 trials are controlled and imply the presence of a control group. ppa, which should not differ significantly from the experimental (basic) either by sex, or by age, or by the initial background treatment. It should be emphasized that background treatment (if possible) should be discontinued 2-4 weeks before the start of the trial. In addition, groups should be formed using randomization, i.e. random distribution method using tables of random numbers.
Phase 3 clinical trials - these are clinical studies of the safety and efficacy of the drug under conditions close to those in which it will be used if it is approved for medical use. That is, during the 3rd phase, significant interactions between the study drug and other drugs are studied, as well as the influence of age, gender, comorbidities, etc. These are usually blind, placebo-controlled studies. during which treatment courses are compared with standard drugs. Naturally, a large number of patients (up to 10,000 people) take part in this phase of CT, which makes it possible to clarify the features of the drug’s action and determine relatively rare side reactions with its long-term use. During the 3rd phase of CT, pharmacoeconomic indicators are also analyzed, which are used later to assess the level of quality of life of patients and their provision with medical care. The information obtained as a result of the Phase 3 studies is fundamental for making a decision on the registration of a drug and the possibility of its medical use.
Thus, the recommendation of a drug for clinical use is considered reasonable if it is more effective; is better tolerated than known drugs; more economically advantageous; has a simpler and more convenient method of treatment; increases the effectiveness of existing drugs in combined treatment. However, the experience of drug development shows that only about 8% of drugs that receive development approval are allowed for medical use.
Phase 4 clinical trials - these are the so-called post-marketing, or post-registration, studies conducted after obtaining regulatory approval for the medical use of the drug. As a rule, CI goes in two main directions. The first is the improvement of dosing regimens, the timing of treatment, the study of interactions with food and other drugs, the evaluation of effectiveness in various age groups, the collection of additional data regarding economic indicators, the study of long-term effects (primarily affecting the decrease or increase in the mortality rate of patients receiving this drug). a drug). The second is the study of new (not registered) indications for prescribing the drug, methods of its use and clinical effects when combined with other drugs. It should be noted that the second direction of the 4th phase is considered as testing a new drug in the early phases of the study.
Schematically, all of the above is shown in the figure.
Types and types of clinical trials: plan, design and structure
The main criterion in determining the type of clinical trials is the presence or absence of control. In this regard, all CTs can be divided into uncontrolled (non-comparative) and controlled (with comparative control). At the same time, a causal relationship between any effect on the body and the response can only be judged on the basis of a comparison with the results obtained in the control group.
Naturally, the results of uncontrolled and controlled studies are qualitatively different. However, this does not mean that uncontrolled studies are not needed at all. Typically, they are designed to identify connections and patterns, which are then proven by controlled studies. In turn, uncontrolled studies are justified in the 1st and 2nd phases of trials, when human toxicity is studied, safe doses are determined, "pilot" studies are carried out, purely pharmacokinetic, as well as long-term post-marketing trials aimed at identifying rare side effects.
At the same time, phase 2 and 3 trials, aimed at proving a certain clinical effect and analyzing the comparative effectiveness of different treatments, by definition should be comparative (ie, have control groups). Thus, the presence of a control group is fundamental to a comparative (controlled) study. In turn, the control groups are classified according to the type of treatment prescribed and the method of selection. According to the type of treatment prescribed, the groups are divided into subgroups receiving placebo, not receiving treatment, receiving different doses of the drug or different treatment regimens and receiving a different active drug. According to the method of selection of patients in the control group, selection is made with randomization from the same population and "external" ("historical"), when the population differs from the population of this study. To minimize errors in the formation of groups, the method of blind research and randomization with stratification are also used.
Randomization is the method of assigning subjects to groups by random sampling (preferably using computer codes based on a sequence of random numbers), while stratification - this is a process that guarantees an even distribution of subjects into groups, taking into account factors that significantly affect the outcome of the disease (age, overweight, medical history, etc.).
blind study assumes that the subject does not know about the method of treatment. At double blind method the researcher does not know about the ongoing treatment, but the monitor does. There is also the so-called “triple blinding” method, when the monitor does not know about the treatment method, but only the sponsor knows. significant impact on the quality of research compliance , i.e. the rigor of following the test regimen on the part of the subjects.
One way or another, for the qualitative conduct of clinical trials, it is necessary to have a well-designed plan and design of the trial with a clear definition of inclusion / exclusion criteria in the study and clinical relevance (significance).
The design elements of a standard clinical trial are presented as follows: the presence of a medical intervention; the presence of a comparison group; randomization; stratification; use of disguise. However, although there are a number of common points in the design, its structure will differ depending on the goals and phase of the clinical trial. Below is the structure of the most commonly used model study models in clinical trials.
1) Scheme of the research model in one group: all subjects receive the same treatment, however, its results are compared not with the results of the control group, but with the results of the initial state for each patient or with the results of the control according to archival statistics, i.e. Subjects are not randomized. Therefore, this model can be used in phase 1 studies or serve as a complement to other types of studies (in particular, to evaluate antibiotic therapy). Thus, the main drawback of the model is the absence of a control group.
2) Diagram of the research model in parallel groups: subjects of two or more groups receive different courses of treatment or different doses of drugs. Naturally, in this case, randomization is carried out (more often with stratification). This type of model is considered the most optimal for determining the effectiveness of treatment regimens. It should be noted that most clinical trials are conducted in parallel groups. Moreover, this type of CT is favored by regulators, so the main phase 3 trials are also conducted in parallel groups. The disadvantage of this type of testing is that it requires more patients and therefore more cost; the duration of research under this scheme is significantly increased.
3)Cross Model Diagram: Subjects are randomized into groups that receive the same course of treatment, but with a different sequence. As a rule, a liquidation (washout, washout) period equal to five half-lives is required between courses in order for patients to return to baseline. Typically, "crossover models" are used in pharmacokinetic and pharmacodynamic studies because they are more cost effective (require fewer patients) and also in cases where clinical conditions are relatively constant over the study period.
Thus, throughout the entire stage of clinical trials, from the moment of planning and ending with the interpretation of the data obtained, one of the strategic places is occupied by statistical analysis. Considering the variety of nuances and specifics of conducting clinical trials, it is difficult to do without a specialist in specific biological statistical analysis.
Bioequivalent Clinical Studies
Clinicians are well aware that drugs that have the same active substances but are produced by different manufacturers (the so-called generic drugs) differ significantly in their therapeutic effect, as well as in the frequency and severity of side effects. An example is the situation with parenteral diazepam. So, neurologists and resuscitators who worked in the 70-90s know that in order to stop convulsions or conduct induction anesthesia, it was enough for the patient to inject 2-4 ml of seduxen (i.e. 10-20 mg diazepam), manufactured by Gedeon Richter (Hungary), while sometimes 6-8 ml of Relanium (i.e. 30-40 mg of diazepam), manufactured by Polfa (Poland), were sometimes not enough to achieve the same clinical effect. . Of all the "diazepams" for parenteral administration, apaurin produced by KRKA (Slovenia) was the most suitable for stopping the withdrawal syndrome. This kind of phenomenon, as well as the significant economic benefits associated with the production of generic drugs, formed the basis for the development and standardization of bioequivalent studies and related biological and pharmacokinetic concepts.
A number of terms should be defined. Bioequivalence is a comparative assessment of the efficacy and safety of two drugs under the same conditions of administration and at the same doses. One of these drugs is the reference or comparator drug (usually a well-known originator or generic drug), and the other is the investigational drug. The main parameter studied in bioequivalent clinical trials is bioavailability (bioavailability) . To understand the significance of this phenomenon, we can recall a situation that is quite common during antibiotic therapy. Before prescribing antibiotics, determine the sensitivity of microorganisms to them. in vitro. For example, sensitivity to cephalosporins in vitro may turn out to be an order of magnitude (i.e. 10 times) higher than to ordinary penicillin, while during therapy in vivo the clinical effect is higher in the same penicillin. Thus, bioavailability is the rate and degree of accumulation of the active substance at the site of its intended action in the human body.
As mentioned above, the problem of bioequivalence of drugs is of great clinical, pharmaceutical and economic importance. Firstly, the same drug is produced by different companies using different excipients, in different quantities and using different technologies. Secondly, the use of generic drugs in all countries is associated with a significant difference in cost between originator drugs and generic drugs. Thus, the total value of sales of generics in the UK, Denmark, the Netherlands in the market of prescription drugs in 2000 amounted to 50-75% of all sales. Here it would be appropriate to give a definition of a generic drug in comparison with the original drug: generic- this is a medicinal analogue of the original drug (manufactured by another company that is not a patent holder), the patent protection of which has already expired. It is typical that a generic drug contains an active substance (active substance) identical to the original drug, but differs in auxiliary (inactive) ingredients (fillers, preservatives, dyes, etc.).
A number of conferences were held to develop and standardize documents for assessing the quality of generic drugs. As a result, the rules for conducting bioequivalence studies were adopted. In particular, for the EU, these are the “State Regulations on Medical Products in the European Union” (the latest edition was adopted in 2001); for the United States, similar rules were adopted in the last edition of 1996; for Russia - on August 10, 2004, the order of the Ministry of Health of the Russian Federation "On conducting qualitative studies of the bioequivalence of medicines" came into force; for the Republic of Belarus - this is Instruction No. 73-0501 dated May 30, 2001 "On registration requirements and rules for conducting the equivalence of generic medicines."
Taking into account a number of provisions from these fundamental documents, it can be stated that Medicinal products are considered bioequivalent if they are pharmaceutically equivalent and their bioavailability (i.e. the rate and extent of absorption of the active substance) is the same and, after administration, they can provide adequate efficacy and safety in the same dose.
Naturally, the performance of bioequivalence studies must comply with the principles of GCP. However, conducting clinical trials on bioequivalence has a number of features. First, studies should be performed in healthy, preferably non-smoking, volunteers of both sexes, aged 18-55 years, with precise inclusion/exclusion criteria and appropriate design (controlled, randomized, cross-over clinical trials). Secondly, the minimum number of subjects is at least 12 people (usually 12-24). Third, the ability to participate in the study must be confirmed by standard laboratory tests, history taking and general clinical examination. Moreover, both before and during the test, special medical examinations can be carried out, depending on the characteristics of the pharmacological properties of the studied drug. Fourthly, for all subjects, appropriate standard conditions should be created for the period of the study, including a standard diet, the exclusion of other drugs, the same motor and daily regimen, a physical activity regimen, the exclusion of alcohol, caffeine, narcotic substances and concentrated juices, time spent at the study center, and end time of the trial. Moreover, it is necessary to study the bioavailability both with the introduction of a single dose of the studied drug, and when reaching a stable state (i.e., a stable concentration of the drug in the blood).
From the pharmacokinetic parameters used to assess bioavailability, the maximum concentration of the drug substance (C max) is usually determined; the time to achieve the maximum effect (T max reflects the rate of absorption and the onset of the therapeutic effect); the area under the pharmacokinetic curve (AUC - area under concentration - reflects the amount of a substance that enters the bloodstream after a single injection of the drug).
Naturally, the methods used to determine bioavailability and bioequivalence must be accurate, reliable and reproducible. According to the WHO regulation (1994, 1996), it is determined that two drugs are considered bioequivalent if they have similar pharmacokinetic parameters and differences between them do not exceed 20%.
Thus, the study of bioequivalence allows making a reasonable conclusion about the quality, efficacy and safety of the compared drugs based on a smaller amount of primary information and in a shorter time than when conducting other types of clinical trials.
When performing studies to study the equivalence of two drugs in a clinical setting, there are situations when a drug or its metabolite cannot be quantified in plasma or urine. In this slu tea is estimated pharmacodynamic equivalence. At the same time, the conditions under which these studies are carried out must strictly comply with the requirements of the GCP. This, in turn, means that the following requirements must be observed when planning, conducting and evaluating results: 1) the measured response must be a pharmacological or therapeutic effect confirming the efficacy or safety of the drug; 2) the method must be validated in terms of accuracy, reproducibility, specificity and validity; 3) the reaction should be measured by a quantitative double-blind method, and the results should be recorded using an appropriate instrument with good reproduction (if such measurements are not possible, data recording is carried out on a scale of visual analogs, and data processing will require special non-parametric statistical analysis (for example, using the Mann test - Whitney, Wilcoxon, etc.) 4) with a high probability of a placebo effect, it is recommended to include a placebo in the treatment regimen; 5) the design of the study should be cross-sectional or parallel.
Closely related to bioequivalence are such concepts as pharmaceutical and therapeutic equivalence.
Pharmaceutical Equivalence refers to a situation where comparable products contain the same amount of the same active substance in the same dosage form, meet the same comparable standards and are used in the same way. Pharmaceutical equivalence does not necessarily imply therapeutic equivalence, as differences in excipients and manufacturing process can lead to differences in drug efficacy.
Under therapeutic equivalence understand such a situation when drugs are pharmaceutically equivalent, and their effects on the body (ie, pharmacodynamic, clinical and laboratory effects) are the same.
Literature
1. Belykh L.N. Mathematical methods in medicine. - M.: Mir, 1987.
2. Valdman A.V.. Experimental and clinical pharmacokinetics: Sat. tr. Research Institute of Pharmacology of the USSR Academy of Medical Sciences. - M.: Medicine, 1988.
3.Loyd E. Handbook of applied statistics. - M., 1989.
4. Maltsev V.I. Clinical trials of drugs. - 2nd ed. - Kyiv: Morion, 2006.
5. Rudakov A.G.. Handbook of clinical trials / trans. from English. - Brookwood Medical Publication Ltd., 1999.
6. Solovyov V.N., Firsov A.A., Filov V.A. Pharmacokinetics (manual). - M.: Medicine, 1980.
7. Stefanov O.V. Doklіnіchnі doslіdzhennya likarskih sobіv (method. recommendations). - Kiev, 2001.
8. Steuper E. Machine analysis of the relationship between chemical structure and biological activity. - M.: Mir, 1987.
9. Darvas F., Darvas L. // Quantitative structure-activity analysis / ed. by R.Franke et al. - 1998. - R. 337-342.
10.Dean P.M. // Trends Pharm. sci. - 2003. - Vol. 3. - P. 122-125.
11. Guideline for Good Clinical Trials. - ICN Harmonized Tripartite Guideline, 1998.
Medical news. - 2009. - No. 2. - S. 23-28.
Attention! The article is addressed to medical specialists. Reprinting this article or its fragments on the Internet without a hyperlink to the original source is considered a copyright infringement.
GENERAL RECIPE.»
1. Definition of the subject of pharmacology and its tasks.
2. Stages of development of pharmacology.
3.Methods for studying pharmacology in Russia.
4. Ways to find medicines.
5. Prospects for the development of pharmacology.
7. The concept of drugs, medicinal substances and dosage forms.
8. Classification of drugs according to the strength of action,
in terms of consistency and application.
9. The concept of galenic and new galenic preparations.
10. The concept of state pharmacology.
Pharmacology is the study of the effects of drugs on the body..
1. Finding new medicines and bringing them to practical medicine.
2. Improvement of existing drugs (obtaining drugs with less pronounced side effects)
3.Search for drugs with a new therapeutic effect.
4. The study of traditional medicine.
The medicine must be: effective, harmless and have an advantage over the drugs of this group.
STAGES OF DEVELOPMENT OF PHARMACOLOGY.
Stage 1- empirical (primitive communal)
Chance discoveries - Chance finds.
2 stage- emperico-mystical (slave-owning)
The appearance of the first dosage forms
(fragrant waters,)
Hippocrates, Paracelsus, Galen.
3 stage- religious - scholastic or feudal.
4 stage- Scientific pharmacology, the end of the 111th century, the beginning of the 1st century.
Stage 1- pre-Petrine
In 1672, a second pharmacy was opened, where there was a taxation (a fee was charged).
Under Peter 1, 8 pharmacies were opened.
2 stage- pre-revolutionary
3 stage- modern
Scientific pharmacology is being formed. The end of the 1111th century and this stage is connected with the opening of medical faculties at universities.
STUDY METHODS.
1. Descriptive. Nestor Maksimovich
2. Experimental: the first laboratory was opened in Tartu.
Founders: Nelyubin, Iovsky, Dybkovsky, Dogel.
3.Experimental-clinical. The first clinics appear.
Botkin, Pavlov, Kravkov.
4. Experimental - clinical. On pathologically altered organs.
Academician Pavlov and Kravkov, they are also the founders
Russian pharmacology.
academician Pavlov - the study of digestion, ANS, CCC.
Kravkov - (Pavlov's student) - published the first textbook on pharmacology,
which has been reprinted 14 times.
5. Experimental - clinical on pathologically altered organs
taking into account the dose.
Nikolaev and Likhachev - introduced the concept of dose.
In 1920 VNIHFI was opened.
In 1930 VILR was opened.
In 1954, the Research Institute of Pharmacology and Chemistry of Therapy in AMS was opened.
Since 1954, the "golden age" of pharmacology begins.
In 1978, at our plant "Medpreparatov" - NIIA. (Biosynthesis)
PRINCIPLES OF CREATING NEW DRUGS.
The resulting drugs are similar to those that exist in the living
body (for example, adrenaline).
2. Creation of new drugs based on biologically known
active substances.
3. Imperial way. Accidental discoveries, finds.
4. Obtaining drugs from the products of fungi and microorganisms
(antibiotics).
5. Obtaining drugs from medicinal plants.
PROSPECTS FOR THE DEVELOPMENT OF PHARMACOLOGY.
1. Raise the level and efficiency of clinical examination.
2. Raise the level and quality of medical care.
3.Create and increase the production of new drugs for the treatment of cancer patients, patients with diabetes mellitus, CCC.
4. To improve the quality of training of middle and top managers.
General recipe -
This is a branch of pharmacology that studies the rules for prescribing, preparing and dispensing drugs to patients.
RECIPE- this is a written request from a doctor, with a request for preparation
and dispensing medicine to the patient.
According to order No. 110 of the Ministry of Health of Russia of 2007 No. 148-1 U / -88, there are three forms of prescription forms.
FORM 107/U- You can write out: one poisonous or no more than two simple or potent.
For simple and potent prescriptions, the prescription is valid for two months, and for potent and alcohol-containing prescriptions, for 10 days.
FORM 148/U- It is issued in two copies with obligatory filling in a carbon copy, for dispensing medicines free of charge or on preferential terms.
The difference between form No. 2 and form No. 3
FORM №1. 1. Clinic stamp or code.
2. Date of issue of the prescription.
3.Name patient, age.
4.Name doctor.
5. The drug is prescribed.
6.Print and signature.
The prescription is a legal document
FORM №2. 1. Stamp and code.
2.Specified: Free.
3. These recipes have their own number.
4. The number of the pension certificate is indicated.
5. Only one medicinal substance is prescribed.
FORM №3. The prescription is written on special forms of moire paper, pink, waves are visible in the light, i.e. This form cannot be faked.
This is a special account form, has a pink color, watermarks and a series
Difference from form No. 3 from other forms of the corresponding forms.
1. Each form has its own series and number (for example, HG - No. 5030)
2. On the prescription form, the number of the medical history or outpatient
3. Forms are stored in safes, they are closed and stamped, i.e. are sealed. Prescription forms are recorded in a special journal, which is numbered, laced and sealed.
4. Responsible for storage carried out by order of the hospital or clinic.
5. Only one substance is prescribed for drugs, it is prescribed only by the doctor himself and is certified by the chief doctor or head. department.
PRESCRIPTION RULES:
The recipe is written only with a ballpoint pen, corrections and strikethroughs are not allowed. Issued only in Latin.
Solid medicinal substances are prescribed in grams (for example: 15.0),
liquid substances are indicated in ml.,
· Ethyl alcohol in its pure form is released from the pharmacy warehouse angro i.e. by weight. and therefore, for accounting, it is written out in prescriptions by weight, i.e. in grams
Common abbreviations are allowed. (see order)
The signature is written in Russian or in the national language. The method of application is indicated.
IT IS FORBIDDEN: in the signature write such expressions as:
internally
or application is known.
Every pharmacy has a log of incorrect prescriptions.
MEDICINAL SUBSTANCE is a substance used to treat
prevention and diagnosis of diseases.
MEDICINE- this is a drug (l.f.) that has one or more medicinal substances in its composition and is produced in a specific dosage form.
PHARMACEUTICAL FORM - it is the form of the drug that makes it convenient to use.
Topic: CLASSIFICATION OF MEDICINES BY
THE POWER OF ACTION.
1.Poisonous and narcotic. (list A. powders)
Designated (Venena "A"), stored in barbells, label - black,
the name of the drug is written in white letters. They are stored in accordance with order No. 328 of 08/23/1999 in safes, under lock and key equipped with sound or light alarms, sealed at night. The key is in the possession of the person responsible for the registration of narcotic substances.
On the inside of the safe door, a list of A - poisonous drugs is indicated, indicating the highest single dose and the highest daily dose. Inside the safe there is a separate place where especially toxic substances (mercuric chloride, arsenic) are stored.
2.Strong
(Heroica "B")
The label on the barbells is white, the names of the substances are written in red letters, they are stored in ordinary cabinets.
3. Preparations of general action.
They are also placed in regular cabinets.
The label is white, written in black letters.
CLASSIFICATION BY CONSISTENCY.
Are divided into:
1.Solid.
CLASSIFICATION BY THE METHOD OF APPLICATION:
1.For outdoor use.
2.For internal use.
3.For injection.
According to the method of manufacturing liquid dosage forms isolated into a special group of drugs, which are called - galenic
GALENIC PREPARATIONS- these are alcohol extracts from medicinal raw materials, containing, together with active substances, also ballast substances. - (substances do not have a therapeutic effect and are also not harmful to the body)
NOVOGALENOV DRUGS:- these preparations are maximally purified
from ballast substances. In its composition, mainly contain pure active ingredients.
ACTIVE SUBSTANCES- these are chemically pure substances of a certain direction of therapeutic action.
BALLAST SUBSTANCES- reduce or increase the effect of therapeutic action without harming health
The STATE PHARMACOPEIA is a collection of general state standards that determine the quality, efficacy and safety of medicines. It contains articles on the determination of the qualitative and quantitative content of substances in dosage forms.
