Stages of development of new drugs. Ways to create a new drug
The development of new drugs includes a number of sequential stages.
First stage aimed at search for promising compounds, possibly having a medicinal effect. The main paths are outlined above.
Second phase- This preclinical study of biological activity substances designated for further study. Preclinical study of the substance is divided into: pharmacological and toxicological.
Target pharmacological research- determination of not only the therapeutic effectiveness of the drug and its effect on the body’s 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. Highlight three stages toxicological studies: 1) study of the toxicity of the drug after a single administration; 2) determination of the chronic toxicity of a substance upon repeated administration for 1 year or more; 3) establishing the specific effect of the compound (oncogenicity, mutagenicity, effect on the fetus, etc.).
The third stage - clinical trials new medicinal substance. Held assessment of therapeutic or prophylactic effectiveness, tolerability, establishing doses and regimens of use of the drug, as well as comparative characteristics with other drugs. During clinical trials, they isolate four phases.
IN phase I establish the tolerability and therapeutic effect of the study drug on a limited number of patients (5-10 people), as well as on healthy volunteers.
IN phase II clinical trials are carried out as 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 leader of the trial, knows which drug is being used. Efficacy and tolerability of a new pharmacological drug compared with those of a placebo or drug of similar effect.
Purpose phase III trials is to obtain additional information about the pharmacological agent being studied. At the same time, research is being conducted on hundreds or even thousands of patients both in 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 drug in practice in a variety of situations, with special attention paid to the collection and analysis of data on the side effects of the drugs under study.
Views: 12173 | Added: March 24, 2013Sources for obtaining medications may be:
- Products of chemical synthesis. Currently, most drugs are obtained this way. There are several ways to find drugs among chemical synthesis products:
- 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. Pharmacological screening was first used by the German scientist Domagk, who worked at the chemical concern IG-FI and searched for antimicrobial agents among compounds synthesized for dyeing fabrics. One of these dyes, red streptocide, has been found to have an antimicrobial effect. This is how sulfonamide drugs were discovered. Conducting screening is an extremely time-consuming and expensive process: to detect one drug, a researcher must test several hundred or thousand compounds. Thus, Paul Ehrlich, when searching 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, to carry out screening, it is necessary to synthesize at least 10,000 initial compounds in order to be confident that among them there is one (!) potentially effective drug.
- Molecular drug design. The creation of scanning tomography and X-ray analysis, the development of computer technologies have made it possible to obtain three-dimensional images of the active centers of receptors and enzymes and to select molecules for them, the configuration of which exactly matches their shape. Molecular design does not require the synthesis of thousands of compounds and their testing. The researcher immediately creates several molecules that are 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 using the molecular design method.
- Reproduction of nutrients. In this way, mediators were obtained - adrenaline, norepinephrine, prostaglandins; drugs with the activity of hormones of the pituitary gland (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 fluoridating cortisol, powerful glucocorticoid drugs were created; by fluoridating 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 it produces a substance with tranquilising activity - oxazepam. Currently, oxazepam is synthesized and released as a separate drug.
- Random finds (“serendipite” method). The method got its name from the fairy tale “The Three Princesses of Serendipe” by Horace Walpole. These sisters often made successful discoveries and found solutions to problems themselves without specifically meaning to. An example of a “serendipitous” drug production is the creation of penicillin, which occurred largely due to the fact that A. Fleming accidentally noticed that microorganisms had died in a moldy cup forgotten in the thermostat at Christmas. Sometimes accidental discoveries are made as a result of error. For example, mistakenly believing that the anticonvulsant effect of phenytoin is due to the fact that it is a folic acid antagonist, employees of the Glaxo Wellcome concern synthesized lamotrigine, a new anticonvulsant. However, it turned out that, firstly, the effect of phenytoin is not associated with folic acid, and secondly, lamotrigine itself does not interfere with folate metabolism.
- Components of plant raw materials. Many plants contain substances that have beneficial pharmacological properties, and the discovery of more and more new compounds continues to this day. Well-known examples of drugs obtained from medicinal plant materials are morphine, isolated from the opium poppy ( Papaversomniferum), atropine derived from belladonna ( Atropabelladonna).
- Animal tissues. Some hormonal drugs are obtained from animal tissues - insulin from the pancreas tissue of pigs, estrogens from the urine of stallions, FSH from the urine of women.
- Products of the vital activity of microorganisms. A number of antibiotics and 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 by-products of petroleum refining and is used as an ointment base.
Each drug, before it begins to be used in practical medicine, must undergo a certain study and registration procedure, which would guarantee, on the one hand, the effectiveness of the drug in the treatment of a given pathology, and on the other hand, its safety. The introduction of medicines is divided into a number of stages (see Table 1).
Diagram 2 shows the main stages of drug movement in the process of its development and study. After completion of phase III clinical trials, the documentation is again received by the Pharmacological Committee (the volume of the complete dossier can be up to 1 million pages) and within 1-2 years is registered in the State Register of Medicines and Medical Products. Only after this does the pharmaceutical concern have the right to begin industrial production of the drug and its distribution through the pharmacy chain.
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 transferred for examination to the Pharmacological Committee, which authorizes the conduct of clinical trials. |
|
| Clinical trials (»8-9 years) Includes 3 phases. The documentation is reviewed by the Pharmacological Committee after completion of each phase. The medicine can be withdrawn at any stage. |
|
Scheme 2. Main stages of research and implementation of medicines in 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 adverse effects of the drug. Participants in this phase include all practitioners who prescribe the drug and the patient who uses it. If serious deficiencies are discovered, the drug may be recalled by the concern. For example, after a new third-generation fluoroquinolone, grepafloxacin, successfully passed all stages of testing and went on sale, the manufacturer recalled the drug less than a year later. Post-marketing studies have found that grepafloxacin may 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 group receiving the study drug, a group should be recruited that receives a standard comparator drug (positive control) or an inactive drug that superficially mimics the study drug (placebo control). This is necessary in order to eliminate the element of self-suggestion when treating with this medicine. Depending on the type of control, there are:
- Single-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 director of the study has information about this.
- Triple-blind study: Neither the patient, the physician, nor the study director knows which group is receiving the new drug and which is receiving the control. Information about this is available from 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 research must be organized in compliance with all ethical standards and principles set out in the Declaration of Helsinki.
Sources for obtaining medications may be:
Products of chemical synthesis. Currently, most drugs are obtained this way. There are several ways to find drugs among chemical synthesis products:
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. Pharmacological screening was first used by the German scientist Domagk, who worked at the chemical concern IG-FI and searched for antimicrobial agents among compounds synthesized for dyeing fabrics. One of these dyes, red streptocide, has been found to have an antimicrobial effect. This is how sulfonamide drugs were discovered. Conducting screening is an extremely time-consuming and expensive process: to discover one drug, a researcher must test several hundred or thousand compounds. Thus, Paul Ehrlich, when searching 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, to carry out screening, it is necessary to synthesize at least 10,000 initial compounds in order to be confident that among them there is one (!) potentially effective drug.
Molecular drug design. The creation of scanning tomography and X-ray analysis, the development of computer technologies have made it possible to obtain three-dimensional images of the active centers of receptors and enzymes and to select molecules for them whose configuration exactly matches their shape. Molecular engineering does not require synthesizing thousands of compounds and testing them. The researcher immediately creates several molecules that are 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 using the molecular design method.
Reproduction of nutrients. In this way, mediator agents were obtained - adrenaline, norepinephrine, prostaglandins; drugs with the activity of hormones of the pituitary gland (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 fluoridating cortisol, powerful glucocorticoid drugs were created; by fluoridating 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 it forms a substance with tranquilising activity - oxazepam. Currently, oxazepam is synthesized and released as a separate drug.
Random finds (“serendipite” method). The method got its name from the fairy tale “The Three Princesses of Serendipe” by Horace Walpole. These sisters often made successful discoveries and found solutions to problems themselves without specifically meaning to. An example of a “serendipitous” drug production is the creation of penicillin, which occurred 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 error. For example, mistakenly believing that the anticonvulsant effect of phenytoin is due to the fact that it is a folic acid antagonist, employees of the GlaxoWellcome concern synthesized lamotrigine, a new anticonvulsant. However, it turned out that, firstly, the effect of phenytoin is not associated with folic acid, and secondly, lamotrigine itself does not interfere with folate metabolism.
Components of plant raw materials. Many plants contain substances that have beneficial pharmacological properties, and the discovery of more and more new compounds continues to this day. Well-known examples of drugs obtained from medicinal plant materials are morphine, isolated from the opium poppy ( Papaver somniferum), atropine derived from belladonna ( Atropa belladonna).
Animal tissues. Some hormonal drugs are obtained from animal tissues - insulin from the pancreas tissue of pigs, estrogens from the urine of stallions, FSH from the urine of women.
Products of the vital activity of microorganisms. A number of antibiotics and 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 by-products of petroleum refining and is used as an ointment base.
Each drug, before it begins to be used in practical medicine, must undergo a certain study and registration procedure, which would guarantee, on the one hand, the effectiveness of the drug in the treatment of a given pathology, and on the other hand, its safety. The introduction of medicines is divided into a number of stages (see Table 1).
Diagram 2 shows the main stages of drug movement in the process of its development and study. After completion of phase III clinical trials, the documentation is again received by the Pharmacological Committee (the volume of the complete dossier can be up to 1 million pages) and within 1-2 years is registered in the State Register of Medicines and Medical Products. Only after this does the pharmaceutical concern have the right to begin industrial production of the drug and its distribution through the pharmacy chain.
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 transferred 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 not rodents). 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 effect (inherited defects in offspring); Carcinogenic effect (tumor transformation of cells). |
|
Clinical trials (8-9 years) Includes 3 phases. The documentation is reviewed by the Pharmacological Committee after completion of each phase. The medicine can be withdrawn at any stage. |
PHASE I. IS THE SUBSTANCE SAFE? The pharmacokinetics and 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 HAVE AN EFFECT IN THE PATIENT'S BODY? Performed on a limited number of patients (100-300 people). The tolerability of therapeutic doses by a sick person and the expected undesirable effects are determined. PHASE III. IS THE SUBSTANCE EFFECTIVE? Performed on a large number of patients (at least 1,000-5,000 people). Determine the severity of the effect, clarify undesirable effects. |
Scheme 2. Main stages of research and implementation of medicines in 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 adverse effects of the drug. Participants in this phase include all practitioners who prescribe the drug and the patient who uses it. If serious deficiencies are discovered, the drug may be recalled by the concern. For example, after a new third-generation fluoroquinolone, grepafloxacin, successfully passed all stages of testing and went on sale, the manufacturer recalled the drug less than a year later. Post-marketing studies have found that grepafloxacin may 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 group receiving the study drug, a group should be recruited that receives a standard comparator drug (positive control) or an inactive drug that superficially mimics the study drug (placebo control). This is necessary in order to eliminate the element of self-suggestion when treating with this medicine. Depending on the type of control, there are:
Single-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 director of the study has information about this.
Triple-blind study: Neither the patient, the physician, nor the study director knows which group is receiving the new drug and which is receiving the control. Information about this is available from 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 research must be organized in compliance with all ethical standards and principles set out in the Declaration of Helsinki.
It is known that in the process of creating new medicines, 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 can the ultimate goal of any pharmaceutical research be achieved - obtaining a new drug.
The subjective factor is determined primarily by the researcher’s desire to deal with a scientific problem, his erudition, qualifications and scientific experience. The objective side of the process is related to the identification of priority and promising research areas that can affect the level of quality of life (i.e., the QoL index), as well as commercial attractiveness.
A detailed consideration of the subjective factor ultimately comes down to finding an answer to one of the most intriguing philosophical questions: what place was assigned to His Majesty Chance in the fact that it was this researcher (or group of researchers) who happened to be at the right time and in the right place to relate to the development of this or that specific drug? One of the striking historical examples of the significance of this factor is the history of A. Fleming’s discovery of antibiotics and lysozyme. 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 note that not a single self-respecting laboratory assistant, much less a bacteriologist, would ever allow himself to have for carrying out experiments, a Petri dish of such cleanliness that mold could grow.” 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 humanity more than ever needed a highly effective antibacterial drug, the thought of providence involuntarily comes to mind.
As for the objective factor, its understanding is more amenable to logical cause-and-effect analysis. This means that at the stage of developing a new drug, the criteria that determine the directions of scientific research come to the fore. The primary factor in this process is the urgent medical need or the opportunity to develop new or improve old treatment, which can ultimately affect the quality of life. A good example is the development of new effective antitumor, cardiovascular, hormonal drugs, and means of combating HIV infection. It would be timely to remind you that indicators of the level of quality of life are a person’s physical and emotional state, 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 treatment of chronic pathology.
The commercial attractiveness of a drug is determined by the incidence rate of a particular pathology, its severity, the amount of treatment costs, the size of the sample of patients suffering from this disease, the duration of the course of therapy, the age of the patients, etc. In addition, there are a number of nuances related to the logistical and financial capabilities of the developer and future manufacturer. This is determined by the fact that, firstly, the developer spends most of the funds allocated for scientific research on maintaining the achieved and strongest positions in the market (where he is already, as a rule, a leader); secondly, the focus of the development of a new drug is the relationship between the expected costs and the actual profit figures that the developer expects to receive from the sale of the drug, as well as the time relationship between these two parameters. Thus, if in 1976 pharmaceutical companies spent an average of about $54 million on research and production 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 increase in costs for the development of new medicines is associated with stricter 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 higher, and in comparison with other industries - 6 times.
Methodology for finding new medicines
In the recent past, the main method of finding new drugs was elementary empirical screening of existing or newly synthesized chemical compounds. Naturally, there cannot be “pure” empirical screening in nature, since any study is ultimately based on previously accumulated factual, experimental and clinical material. A striking historical example of such screening is the search for antisyphilitic drugs conducted by P. Ehrlich among 10 thousand arsenic compounds and ending 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 medicinal 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, direct modeling of structural activity occurs 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., a mediator), suitable for a natural “lock” (i.e., a receptor). The second is the design of a “lock” for the existing natural “key”. Scientific approaches used for these purposes are based on a variety of technologies, ranging from molecular genetics and NMR methods to direct computer modeling of the active molecule in three-dimensional space using CAD (Computer Assisted Design) programs. However, ultimately, the process of designing and synthesizing potential biologically active substances is still based on the intuition and experience of the researcher.
Once a promising chemical compound has been synthesized and its structure and properties have been established, research begins. preclinical stage animal testing. It includes a description of the chemical synthesis process (data on the structure and purity of the drug is provided), experimental pharmacology (i.e. pharmacodynamics), and the study of pharmacokinetics, metabolism and toxicity.
Let us highlight the main priorities of the preclinical stage. For pharmacodynamics is a study of the specific pharmacological activity of a drug and its metabolites (including 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 rate constants of elimination (Kel), absorption (Ka), excretion (Kex), drug clearance, area under the concentration-time curve, etc.); For toxicology- this is the determination of acute and chronic toxicity (on at least two types of experimental animals), carcinogenicity, mutagenicity, teratogenicity.
Experience shows that during testing, approximately half of candidate substances are rejected precisely due to low stability, high mutagenicity, teratogenicity, etc. Preclinical studies, like clinical studies, can be divided into four phases (stages):
Preclinical studies (stage I) (Selection of promising substances)
1.Evaluating patent opportunities and filing a patent application.
2.Basic pharmacological and biochemical screening.
3.Analytical study of the active substance.
4.Toxicological studies to determine 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) (Security Assessment)
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, breakdown 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.
Once, based on the necessary preclinical studies, evidence has been obtained of the safety and therapeutic effectiveness of the drug, as well as the possibility of conducting quality control, the developers complete and submit an application to the permitting 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 an application to the licensing authorities containing the following information: 1) data on the chemical composition of the medicinal product; 2) 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 begin if the following basic requirements are met: information from preclinical trials convincingly shows that the drug can be used in the treatment of this specific pathology; the clinical trial design is adequately designed and, therefore, clinical trials can provide reliable information about the effectiveness and safety of the drug; the drug is safe enough to be tested in humans and subjects will not be exposed to undue risk.
The transition stage from preclinical studies to clinical studies can be schematically represented as follows:
The human clinical trial program for a new drug consists of four phases. The first three are carried out before the drug is registered, and the fourth, called post-registration or post-marketing, is carried out after the drug is registered and approved for use.
Phase 1 clinical trials. Often this phase is also called medical-biological, 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, phase 1 clinical trials (CT) involve healthy volunteers ranging from 80 to 100 people (in our conditions, usually 10-15 young healthy men). An exception is the testing of anticancer drugs and anti-AIDS drugs due to their high toxicity (in these cases, tests are immediately carried out on patients with these diseases). It should be noted that in the 1st phase of the CI, on average, about 1/3 of the candidate substances are eliminated. In fact, the 1st phase of the trial should answer the main question: is it worth continuing 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 to treat a specific pathology. This phase is often called pilot, or pilot, studies, since the results obtained during these tests allow planning of 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 safety of the drug 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 pp, which should not differ significantly from the experimental (main) one in terms of gender, age, or initial background treatment. It should be emphasized that background treatment (if possible) should be stopped 2-4 weeks before the start of the trial. In addition, groups should be formed using randomization, i.e. by random distribution using tables of random numbers.
Phase 3 clinical trials - these are clinical studies of the safety and effectiveness of a drug under conditions similar 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, concomitant diseases, etc. Typically these are blinded, placebo-controlled studies. , during which courses of treatment are compared with standard drugs. Naturally, a large number of patients (up to 10 thousand people) take part in this phase of the clinical trial, which makes it possible to clarify the features of the drug’s action and determine relatively rare adverse reactions with long-term use. During the 3rd phase of the clinical trial, pharmacoeconomic indicators are also analyzed, which are subsequently used to assess the quality of life of patients and their provision of medical care. Information obtained from 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 justified if it is more effective; has better tolerability than known drugs; more economically beneficial; has a simpler and more convenient treatment method; increases the effectiveness of existing drugs in combination treatment. However, drug development experience shows that only about 8% of drugs that receive development approval are approved 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, CIs proceed in two main directions. The first is to improve dosing regimens, treatment timing, study interactions with food and other drugs, evaluate effectiveness in various age groups, collect additional data regarding economic indicators, study long-term effects (primarily affecting the reduction or increase in the mortality rate of patients receiving this drug). a drug). The second is the study of new (unregistered) indications for 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.
All of the above is presented schematically in the figure.
Types and types of clinical trials: design, design and structure
The main criterion in determining the type of clinical trial is the presence or absence of control. In this regard, all clinical trials can be divided into uncontrolled (non-comparative) and controlled (with comparative control). At the same time, the cause-and-effect relationship between any effect on the body and the response can be judged only on the basis of 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 relationships and patterns that are then proven through controlled studies. In turn, uncontrolled studies are justified in phases 1 and 2 trials, when toxicity in humans is studied, safe doses are determined, “pilot” studies, purely pharmacokinetic studies are conducted, 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 treatment methods, by definition must be comparative (i.e., have control groups). Thus, the presence of a control group is fundamental to a comparative (controlled) study. In turn, control groups are classified according to the type of treatment assignment and the method of selection. Based on the type of treatment assignment, the groups are divided into subgroups receiving placebo, receiving no treatment, receiving different doses of the drug or different treatment regimens, and receiving another active drug. According to the method of selecting patients into the control group, a distinction is made between selection with randomization from the same population and “external” (“historical”), when the population differs from the population of this trial. To minimize errors in group formation, a blind study method and randomization with stratification are also used.
Randomization is a method of assigning subjects to groups by random sampling (preferably using computer codes based on a sequence of random numbers), whereas stratification is a process that guarantees an even distribution of subjects into groups, taking into account factors that significantly influence the outcome of the disease (age, excess weight, medical history, etc.).
Blind study assumes that the subject is unaware of the treatment method. At double blind method The researcher does not know about the treatment being carried out, 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 does. The quality of the research has a significant impact compliance , i.e. strict adherence to the test regime on the part of the subjects.
One way or another, for high-quality clinical trials, it is necessary to have a well-written trial plan and design with a clear definition of inclusion/exclusion criteria for the study and clinical relevance (significance).
The design elements of a standard clinical trial are presented as follows: presence of a medical intervention; presence of a comparison group; randomization; stratification; use of disguise. However, although there are a number of commonalities in the design, its design will vary depending on the objectives and phase of the clinical trial. The structure of the most commonly used typical study designs in clinical trials is presented below.
1) Single group study design diagram: All subjects receive the same treatment, but 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 control according to archival statistics, i.e. subjects are not randomized. Therefore, this model can be used in phase 1 studies or complement other types of studies (particularly those evaluating antibiotic therapy). Thus, the main drawback of the model is the lack of a control group.
2) Diagram of the parallel group study model: subjects in two or more groups receive different courses of treatment or different doses of drugs. Naturally, in this case, randomization is carried out (usually 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, regulatory authorities prefer this type of CT, so the main phase 3 studies are also carried out in parallel groups. The disadvantage of this type of trial is that it requires a larger number of patients and therefore higher costs; The duration of research according to this scheme increases significantly.
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 washout period of five half-lives is required between courses in order for patients to return to baseline values. Typically, crossover models are used in pharmacokinetics and pharmacodynamics studies because they are more cost-effective (requiring fewer patients) and when clinical conditions are relatively constant over the study period.
Thus, throughout the entire stage of clinical trials, from the moment of planning to the interpretation of the data obtained, statistical analysis occupies one of the strategic places. 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 (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 diazepam for parenteral administration. Thus, neurologists and resuscitators who worked in the 70-90s know that in order to stop seizures or perform induction anesthesia, it was enough for the patient to inject 2-4 ml of seduxen intravenously (i.e. 10-20 mg diazepam), produced by Gedeon Richter (Hungary), while to achieve the same clinical effect, sometimes 6-8 ml of relanium (i.e. 30-40 mg of diazepam), produced by Polfa (Poland) was not enough . To relieve withdrawal symptoms, of all the “diazepams” for parenteral administration, the most suitable was apaurin produced by KRKA (Slovenia). This phenomenon, as well as the significant economic benefits associated with the production of generic drugs, formed the basis for the development and standardization of bioequivalence studies and associated biological and pharmacokinetic concepts.
A number of terms need to be defined. Bioequivalence is a comparative assessment of the effectiveness and safety of two drugs under the same conditions of administration and in the same doses. One of these drugs is a standard or reference drug (usually a well-known original drug or a generic drug), and the other is an investigational drug. The main parameter studied in bioequivalence clinical studies is bioavailability (bioavailability) . To understand the significance of this phenomenon, we can recall a situation that occurs quite often during antibiotic therapy. Before prescribing antibiotics, determine the sensitivity of microorganisms to them in vitro. For example, sensitivity to cephalosporins in vitro may be an order of magnitude (i.e. 10 times) higher than that of ordinary penicillin, while during therapy in vivo the clinical effect is higher with 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 original drugs and generic drugs. Thus, the total value of sales of generics in the UK, Denmark, and the Netherlands on the prescription drug market in 2000 amounted to 50-75% of all sales. Here it would be appropriate to give the 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 the patent holder), the period of patent protection for 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, rules for conducting bioequivalence studies were adopted. In particular, for the EU these are the “State Regulations on Medical Products in the European Union” (last edition adopted in 2001); for the USA, similar rules were adopted in the latest edition in 1996; for Russia - on August 10, 2004, the order of the Ministry of Health of the Russian Federation “On conducting high-quality 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 drugs are considered bioequivalent if they are pharmaceutically equivalent, and their bioavailability (i.e. the rate and degree of absorption of the active substance) is the same and, after administration, they can provide the required effectiveness and safety in the same dose.
Naturally, the performance of bioequivalence studies must comply with GCP principles. However, conducting clinical trials on bioequivalence has a number of features. First, studies should be carried out in healthy, preferably non-smoking, volunteers of both sexes aged 18-55 years, with precise inclusion/exclusion criteria and an appropriate design (controlled, crossover clinical trials with random assignment of volunteers). Secondly, the minimum number of subjects is at least 12 people (usually 12-24). Thirdly, the ability to participate in the study must be confirmed by standard laboratory tests, medical history 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 drug being studied. Fourthly, appropriate standard conditions must be created for all subjects for the period of research, including a standard diet, exclusion of other medications, the same motor and daily routine, physical activity regime, exclusion of alcohol, caffeine, narcotic substances and concentrated juices, time spent in the research center and time of completion of the trial. Moreover, it is necessary to study bioavailability both when administering a single dose of the drug under study, and when a stable state is achieved (i.e., a stable concentration of the drug in the blood).
Of the pharmacokinetic parameters used to assess bioavailability, the maximum drug concentration (Cmax) is usually determined; time to achieve maximum effect (T max reflects the rate of absorption and onset of the therapeutic effect); area under the pharmacokinetic curve (AUC - area under concentration - reflects the amount of the substance entering the blood after a single administration of the drug).
Naturally, the methods used to determine bioavailability and bioequivalence must be accurate, reliable and reproducible. According to WHO regulations (1994, 1996), it is determined that two drugs are considered bioequivalent if they have similar pharmacokinetic parameters and the differences between them do not exceed 20%.
Thus, a bioequivalence study allows one to make an informed conclusion about the quality, effectiveness and safety of the drugs being compared based on a smaller amount of primary information and in a shorter time than when conducting other types of clinical trials.
When performing equivalence studies between two drugs in a clinical setting, there are situations where the drug or its metabolite cannot be quantitatively determined in blood plasma or urine. In this case tea is estimated pharmacodynamic equivalence. At the same time, the conditions in which these studies are conducted must strictly comply with GCP requirements. This, in turn, means that the following requirements must be met when planning, conducting and evaluating results: 1) the measured response must represent a pharmacological or therapeutic effect that confirms the effectiveness or safety of the drug; 2) the technique must be validated in terms of accuracy, reproducibility, specificity and reliability; 3) the response must be measured quantitatively in a double-blind manner, and the results must be recorded using an appropriate device with good reproducibility (if such measurements are not possible, data recording is carried out using a visual analogue scale, and data processing will require special non-parametric statistical analysis (for example, the use of the Mann test -Whitney, Wilcoxon, etc.); 4) if there is a high probability of a placebo effect, it is recommended to include a placebo in the treatment regimen; 5) the study design should be cross-sectional or parallel.
Closely related to bioequivalence are concepts such as pharmaceutical and therapeutic equivalence.
Pharmaceutical equivalence refers to the situation where the drugs being compared contain the same amount of the same active substance in the same dosage form, meet the same comparable standards and are administered in the same way. Pharmaceutical equivalence does not necessarily imply therapeutic equivalence, since differences in excipients and manufacturing processes may result in differences in drug efficacy.
Under therapeutic equivalence understand a situation where drugs are pharmaceutically equivalent and their effects on the body (i.e. 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: collection. tr. Research Institute of Pharmacology of the USSR Academy of Medical Sciences. - M.: Medicine, 1988.
3.Lloyd E. Handbook of Applied Statistics. - M., 1989.
4. Maltsev V.I.. Clinical drug trials.—2nd ed. - Kyiv: Morion, 2006.
5. Rudakov A.G.. Handbook of clinical trials / trans. from English - Brookwood Medical Publication Ltd., 1999.
6. Soloviev V.N., Firsov A.A., Filov V.A. Pharmacokinetics (guide). - M.: Medicine, 1980.
7. Stefanov O.V. Preclinical studies of medicinal products (methodological recommendations). - Kiev, 2001.
8. Stuper 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. - pp. 23-28.
Attention! The article is addressed to medical specialists. Reprinting this article or its fragments on the Internet without a hyperlink to the source is considered a violation of copyright.
GENERAL RECIPE."
1. Definition of the subject of pharmacology and its tasks.
2. Stages of development of pharmacology.
3.Methods of 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 by strength,
by consistency and application.
9. The concept of galenic and new-galenic preparations.
10. The concept of state pharmacology.
Pharmacology studies the effect of drugs on the body.
1. Finding new medicines and bringing them to practical medicine.
2.Improving existing drugs (obtaining drugs with less pronounced side effects)
3.Search for drugs with new therapeutic effects.
4. Study of traditional medicine.
The medicine must be: effective, harmless and have an advantage over drugs of this group.
STAGES OF PHARMACOLOGY DEVELOPMENT.
Stage 1- empiric (primitive communal)
Random discoveries are random finds.
2nd stage- emperico-mystical (slave-owning)
The appearance of the first dosage forms
(fragrant waters,)
Hippocrates, Paracelsus, Galen.
3rd stage- religious - scholastic or feudal.
4th stage- scientific pharmacology, end of U111 beginning of the 1st century.
Stage 1- pre-Petrine
In 1672, a second pharmacy was opened, where there was a tax (payment was collected).
Under Peter 1, 8 pharmacies were opened.
2nd stage- pre-revolutionary
3rd stage- modern
Scientific pharmacology is being formed. The end of the 16th century and this stage is associated 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 - study of digestion, ANS, CVS.
Kravkov - (Pavlov's student) - published the first textbook on pharmacology,
which was reprinted 14 times.
5. Experimental - clinical on pathologically changed 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 was opened at the Academy of Medical Sciences.
The “golden age” of pharmacology began in 1954.
In 1978, at our Medpreparatov plant - NIIA. (Biosynthesis)
PRINCIPLES OF CREATION OF NEW MEDICINES.
The resulting drugs are similar to those that exist in life
body (for example, adrenaline).
2.Creation of new drugs based on known biologically
active substances.
3.Imperial path. Random discoveries, finds.
4. Obtaining drugs from products of fungi and microorganisms
(antibiotics).
5. Obtaining drugs from medicinal plants.
PROSPECTS FOR THE DEVELOPMENT OF PHARMACOLOGY.
1.Increase the level and efficiency of clinical examination.
2.Raise the level and quality of medical care.
3. Create and increase the production of new medicines for the treatment of cancer patients, patients with diabetes mellitus, CVS.
4.Improve the quality of training for mid- and senior-level personnel.
General recipe –
This is a branch of pharmacology that studies the rules for prescribing, preparing and dispensing medications to patients.
RECIPE- this is a written request from a doctor with a request to prepare
and dispensing medication 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 prescribe: one poisonous or no more than two simple or potent ones.
For simple and strong ones, the prescription is valid for two months, and for strong and alcohol-containing ones - for 10 days.
FORM 148/U- It is written out in two copies with obligatory completion as a carbon copy, for dispensing medications free of charge or on preferential terms.
The difference between form No. 2 and form No. 3
FORM No. 1. 1. Clinic stamp or code.
2.Date of prescription.
3.F.I.O. patient, age.
4.F.I.O. doctor
5. The drug is prescribed.
6.Stamp and signature.
A recipe is a legal document
FORM No. 2. 1.Stamp and code.
2.Indicated: free.
3.These recipes have their own number.
4.Indicate the number of the pension certificate.
5.Only one drug is prescribed.
FORM No. 3. The recipe is written out on special forms made of moire paper, pink in color, waves are visible in the light, i.e. This form cannot be faked.
This is a special accounting 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, ХГ - No. 5030)
2. The number of the medical history or outpatient history is indicated on the prescription form
3. The forms are stored in safes, they are closed and stamped, i.e. are sealed. A record of prescription forms is kept in a special journal, which is numbered, laced and sealed.
4. The person responsible for storage is carried out by order to the hospital or clinic.
5.Only one substance is prescribed for drugs, prescribed only by the doctor himself and certified by the chief physician or manager. department.
RULES FOR WRITING PRESCRIPTIONS:
The prescription is written out only with a ballpoint pen; corrections and crossing-outs 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 sold from the pharmacy warehouse angro i.e. by weight. and therefore, for accounting purposes, it is written out in prescriptions by weight, i.e. in grams
Conventional abbreviations are permitted. (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 expressions such as:
internally
or the use is known.
Every pharmacy has a log of incorrect prescriptions.
DRUG SUBSTANCE is a substance used for treatment,
prevention and diagnosis of diseases.
MEDICINE is a drug (l.f.) containing one or more medicinal substances and produced in a specific dosage form.
DOSAGE FORM - This is a form of a drug that makes it convenient to use.
Topic: CLASSIFICATION OF DRUGS BY
POWER OF ACTION.
1. Poisonous and narcotic. (list A. powders)
They are designated (Venena “A”), stored in standglasses, the label is black,
The name of the drug is written in white letters. 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 held by the person responsible for registering narcotic substances.
On the inside of the safe door there is a list of A - toxic drugs, indicating the highest single dose and the highest daily dose.. Inside the safe there is a separate place where especially toxic substances (sublimate, arsenic) are stored.
2.Potent
(Heroica "B")
The label on the rods is white, the names of the substances are written in red letters, and are stored in ordinary cabinets.
3. General action drugs.
They can also be placed in regular cabinets.
The label is white, written in black letters.
CLASSIFICATION BY CONSISTENCY.
Are divided into:
1.Solid.
CLASSIFICATION BY METHOD OF APPLICATION:
1.For external use.
2.For internal use.
3.For injections.
According to the method of manufacturing liquid dosage forms medicines are classified into a special group, which are called galenic
GALENIC PREPARATIONS- these are alcohol extracts from medicinal raw materials, containing ballast substances along with active ingredients. - (substances do not have a therapeutic effect and are also not harmful to the body)
NEW GALENIC PREPARATIONS:- these drugs are as purified as possible
from ballast substances. They mainly contain pure active ingredients.
ACTIVE SUBSTANCES- these are chemically pure substances with a specific therapeutic effect.
BALLAST SUBSTANCES- reduce or increase the effect of therapeutic action without causing harm to health
STATE PHARMACOPOEIA is a collection of general state standards that determine the quality, effectiveness and safety of medicines. It contains articles on determining the qualitative and quantitative content of substances in dosage forms.
