Clinical trials of medicines. evidence-based medicine. Principles of clinical trials of drugs in children Methods and principles for conducting clinical trials

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Clinical pharmacology L.S. Strachunsky, M.M. shackles
Smolensk State Medical Academy

One of the main types of clinical trials are clinical trials of drugs, the principles of which this article is devoted to.

Doctors and patients want to be sure that prescribed drugs will relieve symptoms or heal the patient. They also want the treatment to be safe. That is why it is necessary to conduct clinical trials in humans. Clinical trials are a necessary part of the process of developing any new drug or expanding indications for the use of a drug already known to doctors. The results of clinical trials are submitted to official authorities. (In our country, this is the Ministry of Health of the Russian Federation and the State Pharmacological Committee and the Institute for Preclinical and Clinical Expertise of Drugs subordinate to it.) If studies have shown that the drug is effective and safe, the Ministry of Health of the Russian Federation gives permission for its use.

The indispensability of clinical trials.

Clinical trials cannot be replaced by studies on tissues (in vitro) or on laboratory animals, including primates. The body of laboratory animals differs from the human body in terms of pharmacokinetic characteristics (absorption, distribution, metabolism and excretion of the drug), as well as in the response of organs and systems to the drug. If a drug causes a drop in blood pressure in a rabbit, this does not mean that it will work to the same extent in humans. In addition, some diseases are unique to humans and cannot be modeled in a laboratory animal. Moreover, even in studies on healthy volunteers, it is difficult to reliably reproduce the effects that a drug will cause in patients.

Clinical research is an inevitable type of scientific activity, without which it is impossible to obtain and select new, more effective and safe drugs, as well as to "purify" medicine from obsolete ineffective drugs. Recently, the role of clinical research has increased due to the introduction of the principles of evidence-based medicine into practical healthcare. Chief among these is making specific clinical decisions for the treatment of a patient not so much on the basis of personal experience or expert opinion, but on the basis of the rigorously proven scientific evidence that can be obtained from well-designed, controlled clinical trials.

The sequence of research.

When studying a new drug, the sequence of research is always observed: from cells and tissues to animals, from animals to healthy volunteers, from a small number of healthy volunteers to patients.

Despite the undoubted limited data obtained from studies on laboratory animals, the drug is being studied on them before it is first used in humans (preclinical trials). Their main goal is to obtain information about the toxicity of a new drug. Acute toxicity with a single dose and subacute toxicity with multiple doses of the drug are studied; investigate mutagenicity, influence on reproductive and immune systems.

Table 1 Phases of clinical trials

Phase	Typical number of patients	Main goals
I	20-80	First use of the drug in humans, assessment of toxicity and safety, determination of pharmacokinetic parameters
II	100-800	Establishment of effectiveness, determination of optimal dosing regimens, safety assessment
III	1000-4000	Confirmation of data on efficacy and safety, comparative studies with standard drugs
IV	Tens of thousands	Further study of efficacy to optimize the use of the drug, long-term safety studies, evaluation of rare adverse drug reactions

Phases of development, drug

Further, clinical studies are carried out, divided into four phases. In table. 1 and the figure shows their main characteristics. As can be seen from the table, the division into phases allows the study of a new drug in humans to be carried out gradually and sequentially. Initially, it is studied in a small number of healthy volunteers (phase I) - (only adults can be volunteers), and then on an increasing number of patients (phases II-III). It is unacceptable to "jump" through the phases of clinical trials, the study goes sequentially from phase I to IV. The goals and objectives of the ongoing tests should change depending on the information obtained in the course of previous studies. Clinical trials may be terminated at any phase if there is evidence of drug toxicity.

Guarantees the rights of patients and compliance with ethical standards,

which are a special case of respect for human rights, are the cornerstone in the entire system of clinical research. They are regulated by international agreements (Declaration of Helsinki of the World Medical Association) and the Russian Federal Law "On Medicines".

At the local level, the guarantor of patient rights is the ethical committee, whose approval must be obtained before all studies are started. It consists of medical and scientific workers, lawyers, clergymen, etc. At their meetings, the members of the ethical committee consider information about the drug, the clinical trial protocol, the text of informed consent and scientific biographies of researchers in terms of risk assessment for patients, observance and guarantee of their rights .

Voluntary participation in clinical trials implies that a patient may participate in a study only with full and informed voluntary consent. Obtaining informed consent from a potential patient is perhaps one of the most difficult tasks facing a researcher. However, in any case, each patient must be fully informed of the consequences of their participation in a clinical trial. Informed written consent, in layman-friendly language, sets out the objectives of the study, the benefits that the patient will receive from participating in it, describes known adverse events associated with the study drug, the terms of the patient's insurance, etc.

The examiner must answer all the patient's questions. The patient should be given the opportunity to discuss the study with family and friends. The Federal Law "On Medicines" states that in the case of a clinical trial in children, such consent must be given by their parents. Conducting clinical trials of medicinal products, including vaccines and sera, on minors without parents is prohibited.

One of the main aspects of protecting the rights of patients is the confidentiality of information relating to the patient. Thus, the patient's personal data (last name, first name, patronymic, place of residence) can only be accessed by persons directly involved in the study. In all documentation, only the individual number of the patient and his initials are noted.

Unity of methodical approach.

All clinical trials must be conducted according to certain rules. A study conducted in Russia should not differ from studies conducted in other countries in terms of methodological approaches, regardless of whether a domestic or foreign drug is being tested, whether the study is sponsored by a pharmaceutical company or a government organization.

Such rules have already been created and are called good clinical practice (QCP), which is one of the possible translations of the English term Good Clinical Practice (GCP) .

The main rules of the CCP

(GCP) are to protect the rights of patients and healthy volunteers participating in a clinical trial, and to obtain reliable and reproducible data. The latter is achieved by observing the following principles: 1) the distribution of responsibilities between the participants in the study; 2) participation of qualified researchers; 3) the presence of external control; 4) scientific approach to research planning, data recording, analysis and presentation of its results.

The rules of the CCP state that when conducting a clinical trial, all duties and responsibilities for the implementation of certain sections of the work must be clearly distributed among all participants in the study even before it begins. There are three main parties involved in the study: the organizer, the researcher and the monitor (a person or group of people who control the direct conduct of the study in the clinic).

Responsibility of the organizers of the study.

The organizers of the study (sponsors) can be pharmaceutical companies or the researchers themselves. The sponsor is responsible for the organization and conduct of the study as a whole. To do this, he must develop a study protocol, provide the researcher with the study drug, manufactured and packaged in accordance with the standards of the CCP, and full information about it. The information should include data from all preclinical and past clinical trials, including details of any adverse drug reactions. Insurance of patients and investigators is also the responsibility of the sponsor.

Responsibility of researchers.

Investigators are primarily responsible for ethical and clinical practice, and for the health and well-being of patients during research. Clinical trials can only be carried out by doctors who have the appropriate qualifications and official permission to practice medicine. The components of the training of investigators are their professional training and special training in clinical trials and the rules of the CCP.

Researchers should always be prepared to conduct quality reviews of their work. Checks are divided into several types: monitoring, audit and inspection. The monitor regularly checks how the ethical standards of the study and the study protocol are observed, as well as the quality of filling out the documentation. The audit is usually carried out only once, in the most important studies. The purpose of the audit is to verify compliance with the rules of the CCP, the protocol and local laws. The duration of the audit depends on the complexity of the study and may take several days. The inspection pursues the same goals, it is carried out by official control and permitting instances.

Research planning.

It is essential that research be designed and conducted in accordance with the latest scientific standards. Formal compliance with the CCP rules does not guarantee that meaningful data will be obtained. Currently, only results obtained from prospective, comparative, randomized, and preferably double-blind studies are taken into account (Table 2). To do this, before the start of the study, a protocol (program) should be developed, which is a written study plan. In table. Section 3 indicates the sections that must be reflected in the protocol.

There are no studies conducted without error, but you should never violate the rules for conducting clinical trials (Table 4).

Table 2. Characteristics of studies

Study	Definition	Target
prospective	Carrying out research according to a predetermined plan	Increased data reliability, as it reduces the likelihood that the observed effect is due to a random combination of events, and not to the study drug. Control for possible systematic errors in the analysis of results
Comparative	Comparison of effects in two groups of patients, one receiving the study drug and the other receiving the comparator drug or placebo	Eliminate the likelihood that an effect is due to spontaneous disease and/or placebo effects
Randomized	Random assignment of patients to treatment and control groups	Eliminate or minimize differences in baseline characteristics between study groups. Basis for the correct application of most statistical tests
double blind	Neither the patient nor the investigator knows whether the patient is receiving an investigational drug or a controlled drug.	Removing bias in evaluating the effect of investigational drugs

Table 3. Main sections of the protocol

Table 4. When conducting clinical trials, you must not:

Conduct research without a carefully designed protocol
Start research without approval of its materials by an independent ethics committee
Include a patient in a study without obtaining written informed consent
Violate protocol requirements during the study:
- include patients who violate the inclusion and exclusion criteria;
- disrupt the schedule of patient visits;
- change the regimen of investigational drugs;
- prescribe prohibited concomitant drugs;
- carry out measurements (examinations) with different devices, violate the examination scheme
Do not report adverse events

Features of clinical trials in children.

Speaking about the conduct of clinical trials in pediatrics, it should be noted that clinical trials of medicinal products in minors are carried out in cases where the investigational medicinal product is intended exclusively for the treatment of childhood diseases or when the purpose of clinical trials is to obtain data on the best dosage of the medicinal product for the treatment of children. Clinical studies of the drug in children should be preceded by clinical studies in adults and a thorough analysis of the data obtained. The results obtained in adults are the basis for planning research in children.

In this case, the complexity of pharmacokinetics, pharmacodynamics and dosing of drugs in children should always be taken into account. Studies of the pharmacokinetics of drugs should be carried out in children of different age groups, taking into account the rapidly changing processes of absorption, distribution, metabolism and excretion of drugs, especially in the neonatal period. When choosing examination methods and target measurements, preference should be given to non-invasive methods, it is necessary to limit the frequency of blood tests in children and the total number of invasive examination methods.

Legal basis for conducting clinical trials.

Conducting clinical trials in our country is regulated by the Federal Law "On Medicines" dated 06/22/1998, which has a separate chapter IX "Development, preclinical and clinical studies of medicines" . According to this law, clinical trials can only be carried out in licensed clinics. Licenses are issued only to those clinics that can ensure the conduct of clinical trials of medicines in accordance with the rules of the CCP.

The Federal Authority for Quality Control of Medicines issues permission for those clinical trials, after which an agreement is concluded between the clinic where the study is planned and the trial organizer. In the event that payment for the test is provided, it can be made by the organizer of the study only by bank transfer, in accordance with the concluded agreement with the clinic.

At the end of our century, everyone began to realize the power of modern drugs, thanks to which not only purely medical problems (reducing the suffering of the patient, saving or prolonging life), but also social problems (improving the quality of life) are solved. Hundreds of new drugs are approved for widespread use each year. Without clinical trials, progress in the development of new drugs is impossible. But nothing: neither the interests of a scientist, nor the interests of a pharmaceutical company, nor the interests of clinical pharmacology as a whole - should be higher than the rights and interests of a child who, in legal terms, can be the subject of research.

Literature

1. The Declaration of Helsinki. Recommendations guiding medical doctors in biomedical research involving human subjects, The World Medical Association, 1964 (revised 1996).
2. Federal Law of 22.06.98. N86 Federal Law "On Medicines" (adopted by the State Duma of the Federal Assembly of the Russian Federation on 06/05/98), Collection of Legislation of the Russian Federation, N26, 06/29/98, article 3006.
3. ICH Topic 6 - Guideline for Good Clinical Practice, Good Clinical Practice J., 1996, v.3, N.4 (Suppl.).

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The concept of clinical research

Any studies of drugs are simply necessary, as one of the stages in the development of a new drug or to expand the indications for the use of an existing one. At first, after receiving the medicine, all studies are carried out on microbiological material and animals. This stage is also called preclinical studies. They are carried out to obtain evidence of the effectiveness of drugs.

But animals are different from humans, so the way mice react to a drug doesn't necessarily mean that people get the same reaction.

If we define what clinical research is, then we can say that this is a system of using various methods to determine the safety and effectiveness of a drug for a person. In the course of studying the drug, all the nuances are clarified:

Pharmacological effect on the body.
absorption rate.
Bioavailability of the drug.
Withdrawal period.
Features of metabolism.
Interaction with other drugs.
Human safety.
Manifestation of side effects.

Laboratory research begins at the decision of the sponsor or customer, who will be responsible not only for organizing, but also for monitoring and financing this procedure. Most often, such a person is the pharmaceutical company that developed this drug.

All results of clinical trials and their course should be described in detail in the protocol.

Research statistics

The study of drugs is carried out all over the world, this is an obligatory stage before the registration of a drug and its mass release for medical use. Those funds that have not passed the study cannot be registered and brought to the drug market.

According to one of the American associations of drug manufacturers, out of 10,000 drugs under investigation, only 250 reach the stage of preclinical studies, as a result, clinical trials will be conducted for only about 5 drugs and 1 will reach mass production and registration. That's the statistics.

Objectives of laboratory research

Conducting research on any drug has several goals:

Determine how safe the drug is for humans. How will the body carry it? To do this, find volunteers who agree to participate in the study.
In the course of the study, optimal doses and treatment regimens are selected to obtain the maximum effect.
To establish the degree of safety of the drug and its effectiveness for patients with a specific diagnosis.
Study of unwanted side effects.
Consider expanding drug use.

Quite often, clinical trials are conducted simultaneously for two or even three drugs, so that their effectiveness and safety can be compared.

Research classification

Such a question as the classification of the study of drugs can be approached from different angles. Depending on the factor, the types of studies may be different. Here are some ways to classify:

By the degree of intervention in the tactics of patient management.
Research may differ in its objectives.

In addition, there are also types of laboratory studies. Let's analyze this issue in more detail.

Varieties of studies on intervention in the treatment of the patient

If we consider the classification in terms of intervention in standard treatment, then studies are divided into:

Observational. In the course of such a study, no interference occurs, information is collected and the natural course of all processes is observed.
Study without intervention or non-interventional. In this case, the drug is prescribed according to the usual scheme. The study protocol does not preliminarily address the issue of attributing the patient to any treatment tactic. Prescription of medication is clearly separated from enrollment of the patient in the study. The patient does not undergo any diagnostic procedures, the data are analyzed using epidemiological methods.
Interventional research. It is carried out when it is necessary to study yet unregistered drugs or to find out new directions in the use of known drugs.

Classification criterion - the purpose of the study

Depending on the purpose, general clinical trials can be:

Preventive. They are carried out in order to find the best ways to prevent diseases in a person that he did not previously suffer from or to prevent relapse. Usually, vaccines and vitamin preparations are studied in this way.
Screening studies provide the best method for detecting diseases.
Diagnostic studies are carried out to find more effective ways and methods for diagnosing the disease.
Therapeutic studies provide an opportunity to study the efficacy and safety of drugs and therapies.

Quality of life studies are conducted to understand how the quality of life of patients with certain diseases can be improved.
Expanded access programs involve the use of an experimental drug in patients with life-threatening conditions. Usually, such drugs cannot be included in laboratory studies.

Research types

In addition to types of research, there are also types that you need to get acquainted with:

A pilot study is carried out to collect the necessary data for the next stages of drug research.
Randomized refers to the distribution of patients randomly into groups, they have the opportunity to receive both the study drug and the control drug.

A controlled drug study investigates a drug whose efficacy is not yet fully known. It is compared with an already well-researched and well-known drug.
An uncontrolled study does not imply the presence of a control group of patients.
A parallel study is conducted simultaneously in several groups of patients who receive the study drug.
In cross-sectional studies, each patient receives both drugs, which are compared.
If the study is open, then all participants know the drug that the patient is taking.
Blind or masked study implies that there are two parties who are not aware of the distribution of patients into groups.
A prospective study is conducted with the distribution of patients into groups, they will either receive or not the study drug before the outcomes occur.
In a retrospective, the outcomes of studies already conducted are considered.
A clinical research center may be involved in one or more, depending on this, there are single-center or multi-center studies.
In a parallel study, the results of several groups of subjects are compared at once, among which one is the control, and two or more others receive the study drug.
A case study involves comparing patients with a particular disease with those who do not have that disease in order to identify an association between outcome and prior exposure to certain factors.

Research stages

After the production of a medicinal product, it must pass all the studies, and they begin with preclinical studies. Conducted on animals, they help the pharmaceutical company understand whether it is worth investigating the drug further.

A drug will only be tested in humans after it has been proven that it can be used to treat a certain condition and is not dangerous.

The development process of any drug consists of 4 phases, each of which is a separate study. After three successful stages, the drug receives a registration certificate, and the fourth is already a post-registration study.

Phase One

A clinical trial of the drug at the first stage is reduced to a set of volunteers from 20 to 100 people. If a drug that is too toxic is being investigated, for example, for the treatment of oncology, then patients suffering from this disease are selected.

Most often, the first phase of the study is carried out in special institutions where there are competent and trained personnel. During this step, you need to find out:

How is the drug tolerated by humans?
pharmacological properties.
The period of absorption and excretion from the body.
Pre-evaluate the safety of its reception.

In the first phase, various types of research are used:

The use of single increasing doses of the drug. The first group of subjects is given a certain dose of the drug, if it is well tolerated, then the next group increases the dosage. This is done until the intended safety levels are reached or side effects begin to appear.
Multiple incremental dose studies. A group of volunteers receives a small drug repeatedly, after each dose, tests are taken, and the behavior of the drug in the body is evaluated. In the next group, an increased dose is repeatedly administered and so on up to a certain level.

Second phase of research

After the safety of the drug has been preliminary assessed, clinical research methods move to the next stage. For this, a group of 50-100 people is already being recruited.

The main goal at this stage of studying the drug is to determine the necessary dosage and treatment regimen. The amount of drug given to patients in this phase is slightly lower than the highest doses given to patients in the first phase.

At this stage, there must be a control group. The effectiveness of the drug is compared either with a placebo or with another drug that has proven to be highly effective in the treatment of this disease.

3 research phase

After the first two phases, drugs continue to be tested in the third phase. A large group of people up to 3000 people participate. The purpose of this step is to confirm the efficacy and safety of the drug.

Also at this stage, the dependence of the result on the dosage of the drug is studied.

After the medicine at this stage confirms its safety and effectiveness, a registration dossier is prepared. It contains information about the results of the study, the composition of the medicine, the expiration date and storage conditions.

Phase 4

This stage is already called post-registration research. The main objective of the phase is to collect as much information as possible about the results of long-term use of the drug by a large number of people.

The question of how drugs interact with other drugs, what is the most optimal duration of therapy, how the drug affects patients of different ages is also being studied.

Study protocol

Any study protocol should contain the following information:

Purpose of drug study.
Challenges faced by researchers.
Study scheme.
Study methods.
Statistical questions.
Organization of the study itself.

The development of the protocol begins even before the start of all studies. Sometimes this process can take several years.

After the study is completed, the protocol is the document by which auditors and inspectors can check it.

Recently, various methods of clinical laboratory research are being used more and more widely. This is due to the fact that the principles of evidence-based medicine are being actively introduced into healthcare. One of them is making decisions for the treatment of a patient based on proven scientific data, and it is impossible to get them without conducting a comprehensive study.

Clinical Study (CT) - is the study of the clinical, pharmacological, pharmacodynamic properties of an investigational drug in humans, including the processes of absorption, distribution, modification and excretion, with the aim of obtaining, by scientific methods, assessments and evidence of the effectiveness and safety of drugs, data on expected side effects and effects of interaction with other drugs.

The purpose of CT of medicines is to obtain, by scientific methods, evaluations and evidence of the efficacy and safety of medicines, data on expected side effects from the use of medicines and the effects of interactions with other medicines.

In the process of clinical trials of new pharmacological agents, 4 interconnected phases:

1. Determine the safety of drugs and establish a range of tolerated doses. The study is carried out on healthy male volunteers, in exceptional cases - on patients.

2. Determine the effectiveness and tolerability of drugs. The minimum effective dose is selected, the breadth of therapeutic action and the maintenance dose are determined. The study is carried out on patients of the nosology for which the study drug is intended (50-300 persons).

3. Clarify the effectiveness and safety of the drug, its interaction with other drugs in comparison with standard methods of treatment. The study is carried out on a large number of patients (thousands of patients), with the involvement of special groups of patients.

4. Post-registration marketing studies study the toxic effects of the drug during long-term use, reveal rare side effects. The study may include different groups of patients - by age, according to new indications.

Types of clinical studies:

Open, when all participants in the trial know which drug the patient is receiving;

Simple "blind" - the patient does not know, but the researcher knows what treatment was prescribed;

In double-blind, neither the research staff nor the patient know whether they are receiving the drug or placebo;

Triple blind - neither the research staff, nor the tester, nor the patient knows what drug he is being treated with.

One of the varieties of clinical trials are bioequivalence studies. This is the main type of control of generic drugs that do not differ in dosage form and content of active substances from the corresponding originals. Bioequivalence studies make it possible to make reasonable

conclusions about the quality of compared drugs based on a smaller amount of primary information and in a shorter time frame. They are carried out mainly on healthy volunteers.

Clinical trials of all phases are being carried out on the territory of Russia. Most of the international clinical trials and trials of foreign medicines belong to the 3rd phase, and in the case of clinical trials of domestic drugs, a significant part of them are phase 4 trials.

In Russia, over the past ten years, a specialized clinical research market. It is well structured, highly qualified professionals work here - research doctors, scientists, organizers, managers, etc., enterprises that build their business on the organizational, service, analytical aspects of conducting clinical trials are actively operating, among them are contract research organizations, medical centers statistics.

Between October 1998 and January 1, 2005, paperwork was filed requesting permission for 1,840 clinical trials. In 1998-1999 domestic companies accounted for an extremely small proportion of applicants, but since 2000 their role has noticeably increased: in 2001 there were 42%, in 2002 - already 63% of applicants, in 2003 - 45.5%. Among the foreign countries-applicants excel Switzerland, USA, Belgium, Great Britain.

The object of study of clinical trials are drugs of both domestic and foreign production, the scope of which affects almost all known branches of medicine. The greatest number of medicines is used for the treatment of cardiovascular and oncological diseases. This is followed by areas such as psychiatry and neurology, gastroenterology, and infectious diseases.

One of the trends in the development of the clinical trials sector in our country is the rapid growth in the number of clinical trials for the bioequivalence of generic drugs. Obviously, this is quite consistent with the peculiarities of the Russian pharmaceutical market: as you know, it is a market for generic drugs.

Conducting clinical trials in Russia is regulatedthe Constitution of the Russian Federation, which states that "... no one

may be subjected to medical, scientific and other experiments without voluntary consent.

Some articles Federal Law "Fundamentals of the legislation of the Russian Federation on the protection of the health of citizens"(dated July 22, 1993, No. 5487-1) determine the basis for conducting a clinical trial. Thus, Article 43 states that medicines that are not approved for use, but are being considered in the prescribed manner, can be used in the interests of curing a patient only after obtaining his voluntary written consent.

Federal Law "On Medicines" No. 86-FZ has a separate chapter IX "Development, preclinical and clinical studies of medicines" (articles 37-41). It specifies the procedure for making a decision to conduct a clinical trial of drugs, the legal basis for conducting clinical trials and the issues of financing clinical trials, the procedure for their conduct, the rights of patients participating in clinical trials.

Clinical trials are conducted in accordance with the Industry Standard OST 42-511-99 "Rules for conducting high-quality clinical trials in the Russian Federation"(approved by the Ministry of Health of Russia on December 29, 1998) (Good Clinical Practice - GCP). The Rules for Conducting Quality Clinical Trials in the Russian Federation constitute an ethical and scientific standard for the quality of planning and conducting research on humans, as well as documenting and presenting their results. Compliance with these rules serves as a guarantee of the reliability of the results of clinical trials, the safety, protection of the rights and health of the subjects in accordance with the fundamental principles of the Declaration of Helsinki. The requirements of these Rules must be observed when conducting clinical trials of medicinal products, the results of which are planned to be submitted to licensing authorities.

The GCPs establish requirements for planning, conducting, documenting, and controlling clinical trials designed to protect the rights, safety, and health of individuals participating in them, in which undesirable effects on human safety and health cannot be excluded, and to ensure the reliability and accuracy of the results obtained. while researching information. The Rules are binding on all participants in clinical trials of medicinal products in the Russian Federation.

In order to improve the methodological foundations for conducting bioequivalence studies of drugs, which are the main type of biomedical control of generic drugs, the Ministry of Health and Social Development of the Russian Federation on August 10, 2004 approved guidelines "Conducting qualitative clinical studies of the bioequivalence of drugs."

According to the regulations, CT tests are carried out in health care institutions accredited by the federal executive body, whose competence includes the implementation of state control and supervision in the field of circulation of medicines; it also draws up and publishes a list of health care institutions that have the right to conduct clinical trials of medicines.

The legal basis for conducting CT LS make a decision of the federal executive body, whose competence includes the implementation of state control and supervision in the field of circulation of medicines, on the conduct of a clinical trial of a medicinal product and an agreement on its conduct. The decision to conduct a clinical trial of a drug is made by the Federal Service for Surveillance in Healthcare and Social Development of the Russian Federation in accordance with the Law "On Medicines" and on the basis of an application, a positive opinion of the ethics committee under the federal authority for quality control of medicines, a report and conclusion on preclinical studies and instructions for the medical use of the medicinal product.

An Ethics Committee has been set up under the federal agency for drug quality control. The health care facility will not commence a study until the Ethics Committee has approved (in writing) the written informed consent form and other materials provided to the subject or their legal representative. The informed consent form and other materials may be revised during the course of the study if circumstances are discovered that may affect the consent of the subject. A new version of the documentation listed above must be approved by the Ethics Committee, and the fact of bringing it to the subject must be documented.

For the first time in world practice, state control over the conduct of clinical trials and observance of the rights of participants in the experiment was developed and implemented in Prussia. On October 29, 1900, the Ministry of Health ordered university clinics to conduct clinical experiments, subject to the obligatory condition of prior written consent from patients. In the 1930s With regard to human rights, the situation in the world has changed dramatically. In concentration camps for prisoners of war in Germany and Japan, experiments on people were carried out on such a large scale that over time, each concentration camp even defined its own “specialization” in medical experiments. Only in 1947 did the international Military Tribunal return to the problem of protecting the rights of people participating in clinical trials. In the process of his work, the first international code was developed Code of Practice for Human Experimentation the so-called Nuremberg Code.

In 1949, the International Code of Medical Ethics was adopted in London, proclaiming the thesis that “the doctor should act only in the interests of the patient, providing medical care that should improve the physical and mental condition of the patient”, and the Geneva Convention of the World Association of Physicians (1948 -1949), defined the doctor's duty with the words: "Caring for the health of my patient is my first task."

The turning point in establishing the ethical basis for clinical trials was the adoption by the 18th General Assembly of the World Medical Association in Helsinki in June 1964. Declaration of Helsinki World Medical Association, which has absorbed the entire world experience in the ethical content of biomedical research. Since then, the Declaration has been revised several times, most recently in Edinburgh (Scotland) in October 2000.

The Declaration of Helsinki states that biomedical research involving humans must comply with generally accepted scientific principles and be based on adequately conducted laboratory and animal experiments, as well as on sufficient knowledge of the scientific literature. They must be carried out by qualified personnel under the supervision of an experienced physician. In all cases, the doctor is responsible for the patient, but not the patient himself, despite the informed consent given by him.

In any research involving human subjects, each potential participant must be adequately informed about the aims, methods, expected benefits of the research, and the associated risks and inconveniences. People should be informed that they have the right to abstain from participation in the study and may, at any time after the study has begun, withdraw their consent and refuse to continue the study. The physician must then obtain freely given informed consent in writing from the subject.

Another important document defining the ethical standards for conducting clinical trials was "International Guidelines for the Ethics of Biomedical Research with Human Involvement", adopted by the Council of International Organizations for Medical Sciences (CIOMS) (Geneva, 1993), which provides recommendations to researchers, sponsors, healthcare professionals and ethical committees on how to implement ethical standards in the field of medical research, as well as ethical principles that apply to all individuals, including patients, participating in clinical trials.

The Declaration of Helsinki and the International Guidelines for the Ethics of Biomedical Research with Human Involvement show how fundamental ethical principles can be effectively applied to the practice of medical research around the world, taking into account the different characteristics of cultures, religions, traditions, social and economic conditions, laws, administrative systems and other situations that may occur in countries with limited resources.

On November 19, 1996, the Parliamentary Assembly of the Council of Europe adopted "Convention for the Protection of Human Rights and Human Dignity with regard to the Application of Biology and Medicine". The norms laid down in the Convention have not only the force of a moral appeal - each state that has acceded to it undertakes to embody "its main provisions in national legislation." According to the provisions of this Convention, the interests and welfare of the individual prevail over the interests of society and science. All medical intervention, including intervention for research purposes, must be carried out in accordance with professional requirements and standards. The subject is obliged to obtain in advance appropriate information about the purpose and nature of the intervention, as well as about

its consequences and risks; his consent must be voluntary. Medical intervention in relation to a person who is not able to give consent to this may be carried out exclusively in his immediate interests. On January 25, 2005, an Additional Protocol to the Convention concerning biomedical research was adopted.

To ensure the observance of the rights of the subjects, the international community has now developed an effective system of public and state control over the rights and interests of research subjects and the ethics of clinical trials. One of the main links in the system of public control is the activity of independent ethical committees(EC).

Ethics committees are today structures that intersect scientific interests, medical facts and moral and legal norms. Ethics committees carry out the functions of examination, consultation, recommendations, motivation, evaluation, orientation in the moral and legal issues of CT. Ethical committees play a crucial role in determining that research is safe, conducted in good faith, that the rights of the patients participating in it are respected, in other words, these committees guarantee the society that every clinical research conducted meets ethical standards.

ECs must be independent of researchers and should not receive material benefits from ongoing research. The researcher must obtain advice, favorable feedback, or committee approval before starting work. The Committee exercises further control, may amend the protocol and monitor the progress and results of the study. Ethical committees should have the power to ban research, terminate research, or simply reject or terminate a permit.

The main principles of the work of ethics committees in the implementation of ethical review of clinical trials are independence, competence, openness, pluralism, as well as objectivity, confidentiality, collegiality.

ECs should be independent of the authorities that decide on conducting clinical trials, including government agencies. An indispensable condition for the competence of the committee is the high qualification and accurate work of its protocol group (or

secretariat). The openness of the work of the ethics committee is ensured by the transparency of the principles of its work, regulations, etc. Standard operating procedures should be open to anyone who wishes to review them. The pluralism of the ethics committee is guaranteed by the heterogeneity of professions, age, gender, confessions of its members. In the process of examination, the rights of all participants in the study, in particular, not only patients, but also doctors, should be taken into account. Confidentiality is required in relation to the materials of the CT, the persons participating in it.

An independent ethics committee is usually created under the auspices of the national or local health departments, on the basis of medical institutions or other national, regional, local representative bodies - as a public association without forming a legal entity.

The main goals of the ethics committee are the protection of the rights and interests of subjects and researchers; impartial ethical evaluation of clinical and preclinical studies (trials); ensuring the conduct of high-quality clinical and preclinical studies (tests) in accordance with international standards; providing public confidence that all ethical principles will be guaranteed and respected.

To achieve these goals, the ethics committee must solve the following tasks: independently and objectively assess the safety and inviolability of human rights in relation to the subjects, both at the planning stage and at the stage of the study (testing); assess the compliance of the study with humanistic and ethical standards, the feasibility of conducting each study (test), the compliance of researchers, technical means, the protocol (program) of the study, the selection of study subjects, the quality of randomization with the rules for conducting high-quality clinical trials; monitor compliance with quality standards for clinical trials to ensure the reliability and completeness of the data.

Assessment of the risk-benefit ratio is the most important ethical decision that the EC makes when reviewing research projects. To determine the reasonableness of the risks in relation to the benefits, a number of factors must be taken into account, and each case should be considered individually, taking

taking into account the characteristics of the subjects participating in the study (children, pregnant women, terminally ill patients).

In order to assess the risks and expected benefits, the EC must ensure that:

The necessary data cannot be obtained without the involvement of people in the study;

The study is rationally designed to minimize discomfort and invasive procedures for subjects;

The study serves to obtain important results aimed at improving the diagnosis and treatment or contributing to the generalization and systematization of data on diseases;

The study is based on the results of laboratory data and animal experiments, in-depth knowledge of the history of the problem, and the expected results will only confirm its validity;

The expected benefit of the study outweighs the potential risk, and the potential risk is minimal; no more than when performing conventional medical and diagnostic procedures for this pathology;

The investigator has sufficient information about the predictability of any possible adverse effects of the study;

The subjects and their legal representatives are provided with all the information necessary to obtain their informed and voluntary consent.

Clinical research should be carried out in accordance with the provisions of international and national legislative documents that guarantee protection of the rights of the subject.

The provisions written in the Convention on the Protection of Human Rights guard the dignity and individual integrity of a person and guarantee everyone, without exception, respect for the inviolability of the person and other rights and fundamental freedoms in connection with the application of the achievements of biology and medicine, including in the field of transplantology, genetics, psychiatry and others

No human study can be conducted without all of the following conditions being met at the same time:

There are no alternative research methods comparable in their effectiveness;

The risk to which the subject may be exposed does not outweigh the potential benefit of conducting the study;

The design of the proposed study was approved by the competent authority after an independent review of the scientific validity of the study, including the importance of its purpose, and a multilateral review of its ethical acceptability;

The person acting as a test subject is informed about his rights and guarantees provided for by law;

Written informed consent for the experiment was obtained, which can be freely withdrawn at any time.

The Fundamentals of the Legislation of the Russian Federation on the Protection of the Health of Citizens and the Federal Law "On Medicines" stipulate that any biomedical research involving a person as an object must be carried out only after obtaining the written consent of a citizen. A person cannot be forced to participate in a biomedical research study.

Upon receipt of consent for biomedical research, a citizen must be provided with information:

1) on the medicinal product and the nature of its clinical trials;

2) the expected efficacy, the safety of the medicinal product, the degree of risk for the patient;

3) about the actions of the patient in case of unforeseen effects of the influence of the medicinal product on his state of health;

4) the terms and conditions of the patient's health insurance.

The patient has the right to refuse to participate in clinical trials at any stage of their conduct.

Information about the study should be communicated to the patient in an accessible and understandable form. It is the responsibility of the investigator or his collaborator, prior to obtaining informed consent, to give the subject or his representative sufficient time to decide whether to participate in the study and provide an opportunity to obtain detailed information about the trial.

Informed consent (informed patient consent) ensures that prospective subjects understand the nature of the study and can make informed and voluntary decisions.

about their participation or non-participation. This guarantee protects all parties: both the subject, whose autonomy is respected, and the researcher, who otherwise comes into conflict with the law. Informed consent is one of the main ethical requirements for human research. It reflects the fundamental principle of respect for the individual. The elements of informed consent include full disclosure, adequate understanding, and voluntary choice. Various population groups may be involved in medical research, but it is prohibited to conduct clinical trials of medicines on:

1) minors without parents;

2) pregnant women, except for cases where clinical trials of drugs intended for pregnant women are being conducted and when the risk of harm to a pregnant woman and fetus is completely excluded;

3) persons serving sentences in places of deprivation of liberty, as well as persons in custody in pre-trial detention centers without their written informed consent.

Clinical trials of drugs in minors are allowed only when the investigational drug is intended solely for the treatment of childhood diseases or when the purpose of clinical trials is to obtain data on the best dosage of the drug for the treatment of minors. In the latter case, clinical trials in children should be preceded by similar trials in adults. In Art. 43 of the Fundamentals of the legislation of the Russian Federation “on the protection of the health of citizens” notes: “The methods of diagnostics, treatment and medicines that are not allowed for use, but are under consideration in the prescribed manner, can be used to treat persons under the age of 15 years, only with an immediate threat to their lives. and with the written consent of their legal representatives. Information about the study should be communicated to children in a language that is accessible to them, taking into account their age. Signed informed consent can be obtained from children who have reached the appropriate age (from 14 years old, as determined by law and ethical committees).

Clinical trials of drugs intended for the treatment of mental illness are allowed on persons with mental illness and recognized as incompetent in the manner

established by the Law of the Russian Federation No. 3185-1 of July 2, 1992 "On psychiatric care and guarantees of the rights of citizens in its provision." Clinical trials of medicines in this case are carried out with the written consent of the legal representatives of these persons.

When using drugs, the effectiveness should exceed the potential risk of side effects (adverse reactions). The "clinical impression" of a drug's efficacy can be misleading, partly due to the subjectivity of the physician and the patient, as well as the bias of the evaluation criteria.

Clinical trials of drugs serve as the basis for evidence-based pharmacotherapy. Clinical study - any study of a drug conducted to obtain evidence of its safety and efficacy with the participation of people as subjects, aimed at identifying or confirming the pharmacological effect, adverse reactions, the study of pharmacokinetics. However, before the start of clinical trials, a potential drug goes through a difficult stage of preclinical studies.

Preclinical studies

Regardless of the source of receipt, the study of a biologically active substance (BAS) is to determine its pharmacodynamics, pharmacokinetics, toxicity and safety.

To determine the activity and selectivity of the action of the substance, various screening tests are used, carried out in comparison with the reference drug. The choice and number of tests depend on the objectives of the study. So, to study potential antihypertensive drugs that act presumably as antagonists of a-adrenergic receptors of blood vessels, they study in vitro binding to these receptors. Next, the antihypertensive activity of the compound is studied in animal models of experimental arterial hypertension, as well as possible side effects. As a result of these studies, it may be necessary to chemically modify the molecules of the substance to achieve more desirable pharmacokinetic or pharmacodynamic properties.

Next, a toxicological study of the most active compounds is carried out (determination of acute, subchronic and chronic toxicity), their carcinogenic properties. The determination of reproductive toxicity is carried out in three phases: the study of the overall effect on fertility and reproductive properties of the organism; possible mutagenic, teratogenic properties of drugs and embryotoxicity, as well as effects on implantation and embryogenesis; long-term studies on peri- and postnatal development. The possibilities for determining the toxic properties of drugs are limited and expensive. It should be borne in mind that the information obtained cannot be fully extrapolated to humans, and rare side effects are usually detected only at the stage of clinical trials. Currently, cell cultures (microsomes, hepatocytes, or tissue samples) are sometimes used as an alternative to experimental preclinical evaluation of the safety and toxicity of drugs in animals.

The final task of preclinical studies is the choice of a method for the production of an investigational drug (eg, chemical synthesis, genetic engineering). An obligatory component of preclinical drug development is the development of a dosage form and assessment of its stability, as well as analytical control methods.

Clinical researches

To the greatest extent, the influence of clinical pharmacology on the process of creating new drugs is manifested in clinical trials. Many results of pharmacological studies in animals used to be automatically transferred to humans. Then, when the need for human studies was recognized by everyone, clinical trials were usually carried out on patients without their consent. Known cases of deliberately dangerous research on socially unprotected persons (prisoners, mentally ill, etc.). It took a long time for the comparative design of the study (the presence of an "experimental" group and a comparison group) to become generally accepted. It is likely that it was mistakes in research planning and analysis of their results, and sometimes falsification of the latter, that caused a number of humanitarian disasters associated with the release of toxic drugs, for example, a solution of sulfanilamide in ethylene glycol (1937), as well as thalidomide (1961), which was prescribed as an antiemetic in early pregnancy. At this time, doctors did not know about the ability of thalidomide to inhibit angiogenesis, which led to the birth of more than 10,000 children with phocomelia (a congenital anomaly of the lower extremities). In 1962, thalidomide was banned for medical use. In 1998, thalidomide was approved by the US FDA (Food and Drug Administration) for use in the treatment of leprosy, and is currently undergoing clinical trials for the treatment of refractory multiple myeloma and glioma. The first government agency to regulate clinical trials was the US FDA, which proposed in 1977. the concept of good clinical practice (Good Clinical Practice, GCP). The most important document defining the rights and obligations of participants in clinical trials was the Helsinki Declaration of the World Medical Association (1968). After numerous revisions, the final document appeared - the Guidelines for Good Clinical Practice (ICH Guidelines for Good Clinical Practice, ICH GCP). The provisions of the ICH GCP are consistent with the requirements for conducting clinical trials of drugs in the Russian Federation and are reflected in the Federal Law "On Medicines" (No. 86-FZ of 06/22/98, as amended on 01/02/2000). Another official document regulating the conduct of clinical trials in the Russian Federation is the industry standard "Rules for conducting high-quality clinical trials in the Russian Federation".

According to these documents, good clinical practice is understood as “a standard for planning, executing, monitoring, auditing and documenting clinical trials, as well as processing and reporting their results; a standard that serves as a guarantee for society of the reliability and accuracy of the data obtained and the results presented, as well as the protection of the rights, health and anonymity of research subjects.

The implementation of the principles of good clinical practice ensures compliance with the following basic conditions: the participation of qualified investigators, the distribution of responsibilities between study participants, a scientific approach to study design, data recording and analysis of the results presented.

The execution of clinical trials at all its stages is subject to multilateral control by the customer of the study, audit, state control bodies and an independent ethical committee, and all activities as a whole are carried out in accordance with the principles of the Declaration of Helsinki.

When conducting clinical trials in humans, the researcher solves three main tasks:

1. Determine how pharmacological effects identified in animal experiments correspond to data that can be obtained when using drugs in humans;

2. Show that the use of drugs has a significant therapeutic effect;

3. Prove that the new drug is safe enough to be used in humans.

Ethical and legal standards of clinical research. Ensuring patient rights and ethical compliance is a complex issue in clinical trials. They are regulated by the above documents, the Ethics Committee serves as a guarantor of the observance of the rights of patients, the approval of which must be obtained before the start of clinical trials. The main task of the Committee is to protect the rights and health of the subjects, as well as guarantee their safety. The ethics committee reviews drug information, evaluates the structure of the clinical trial protocol, the content of the informed consent and biographies of the investigators, followed by an assessment of the potential risk to patients and compliance with their guarantees and rights.

The patient may participate in clinical trials only with full and informed voluntary consent. Each patient must be fully informed of the possible consequences of their participation in a particular clinical trial. He signs an informed written consent, which sets out the goals of the study, its benefits for the patient if he participates in the study, unwanted adverse reactions associated with the study drug, providing the subject with the necessary medical care if they are detected during the trial, information about insurance. An important aspect of protecting the rights of the patient is the observance of confidentiality.

Participants in a clinical study. The first link in clinical trials is the drug developer or sponsor (usually a pharmaceutical company), the second is the medical institution on the basis of which the test is carried out, and the third is the patient. Contract research organizations can act as a link between the customer and the medical institution, assuming the tasks and responsibilities of the sponsor and exercising control over this study.

Conducting clinical trials. The reliability of clinical trial results depends entirely on how carefully they are planned, conducted, and analyzed. Any clinical trial should be carried out according to a strictly defined plan (research protocol), which is identical for all medical centers participating in it.

The study protocol includes a description of the purpose and design of the study, criteria for inclusion (and exclusion) in the trial and evaluation of the effectiveness and safety of the treatment, treatment methods for study subjects, as well as methods and timing for assessing, recording and statistical processing of efficacy and safety indicators.

The objectives of the test must be clearly stated. When testing a medicinal product, this is usually the answer to the question: “How effective is this therapeutic approach under certain conditions in comparison with other therapeutic methods or no therapy at all?”, As well as an assessment of the benefit / risk ratio (at least in terms of reporting the frequency of adverse reactions) . In some cases, the goal is narrower, such as determining the optimal dosing regimen for the drug. Regardless of the goal, it is necessary to clearly articulate what end result will be quantified.

The ICH GCP rules do not allow the use of material incentives to attract patients to participate in the study (with the exception of healthy volunteers involved in the study of pharmacokinetics or bioequivalence of drugs). The patient must meet the exclusion criteria.

Usually, pregnant, breastfeeding, patients with severe liver and kidney dysfunction, aggravated by an allergic history are not allowed to participate in studies. It is unacceptable to include in the study incapable patients without the consent of the trustees, as well as military personnel, prisoners.

Clinical trials in juvenile patients are performed only when the investigational drug is intended exclusively for the treatment of childhood diseases or the study is conducted to obtain information about the optimal dosage of the drug for children. Preliminary studies of this drug in adults or adults with a similar disease are needed, the results of which serve as the basis for planning studies in children. When studying the pharmacokinetic parameters of drugs, it should be remembered that as the child grows, the functional parameters of the child's body change rapidly.

The study should include patients with a clearly verified diagnosis and exclude patients who do not meet predetermined criteria for diagnosis.

Usually, patients with a certain risk of adverse reactions are excluded from the study, for example, patients with bronchial asthma when testing new (3-blockers, peptic ulcer - new NSAIDs.

The study of the action of drugs in elderly patients is associated with certain problems due to the presence of concomitant diseases in them that require pharmacotherapy. In this case, drug interactions may occur. It should be borne in mind that side effects in elderly patients may occur earlier and at lower doses than in middle-aged patients (for example, only after widespread use of the NSAID benoxaprofen was it found to be toxic to elderly patients at doses relatively safe for younger patients). ).

The study protocol for each group of subjects should provide information about drugs, doses, routes and methods of administration, periods of treatment, drugs, the use of which is allowed (including emergency therapy) or excluded by the protocol.

In the section of the protocol “Evaluation of effectiveness”, it is necessary to list the criteria for evaluating the effectiveness, methods and terms for registering its indicators. For example, when testing a new antihypertensive drug in patients with arterial hypertension, 24-hour blood pressure monitoring, measurement of systolic and diastolic pressure in the patient’s lying and sitting position are used as effectiveness criteria (in addition to the dynamics of clinical symptoms), while mean diastolic pressure in the patient’s position is considered effective. seated less than 90 mmHg Art. or a decrease in this indicator by 10 mm Hg. Art. and more after the end of treatment compared with the original figures.

The safety of drugs is assessed throughout the study by analyzing physical data, anamnesis, performing functional tests, ECG, laboratory tests, measuring pharmacokinetic parameters, recording concomitant therapy, and side effects. Information about all adverse reactions noted during the study should be entered in the individual registration card and the adverse event card. Adverse event - any undesirable change in the patient's condition, different from the state before the start of treatment, related or not related to the study drug or any other drug used in concomitant drug therapy.

Statistical processing of clinical trial data is necessary, since usually not all objects of the population of interest are studied, but a random selection of options is carried out. The methods intended for solving this statistical problem are called randomization methods, that is, the distribution of subjects into experimental and control groups randomly. The randomization process, duration of treatment, sequences of treatment periods, and trial termination criteria are reflected in the study design. Closely related to the problem of randomization is the problem of study blindness. The purpose of the blind method is to eliminate the possibility of the influence (conscious or accidental) of a doctor, researcher, patient on the results obtained. The ideal is a double-blind test where neither the patient nor the doctor knows what treatment the patient is receiving. To exclude a subjective factor influencing treatment, a placebo (“dummy”) is used during clinical trials, which makes it possible to distinguish between the actual pharmacodynamic and suggestive effects of the drug, to distinguish the effect of drugs from spontaneous remissions during the course of the disease and the influence of external factors, to avoid obtaining false negative conclusions ( for example, equal efficacy of the study drug and placebo may be due to the use of an insufficiently sensitive method of evaluating the effect or a low dose of the drug).

The individual registration card serves as an information link between the investigator and the trial sponsor and includes the following mandatory sections: screening, inclusion/exclusion criteria, visiting blocks, prescribing the investigational drug, prior and concomitant therapy, registration of adverse drug reactions and completion of the clinical trial.

Phases of clinical research. Clinical trials of drugs are carried out in healthcare institutions licensed to conduct them. Persons participating in clinical trials should receive special training in the conduct of high-quality clinical trials. Control over the testing is carried out by the Department of State Control of Medicines and Medical Equipment.

The sequence of studying drugs is divided into four phases (Table 9-1).

Table 9-1. Phases of clinical trials

Phase I is the initial stage of clinical trials, exploratory and especially carefully controlled. Usually 20-50 healthy volunteers take part in this phase. The purpose of phase I is to determine the tolerability of the drug, its safety in short-term use, the expected efficacy, pharmacological effects and pharmacokinetics, as well as obtaining information on the maximum safe dose. The test compound is administered in low doses with a gradual increase until signs of toxic effects appear. The initial toxic dose is determined in preclinical studies; in humans, it is 100 experimental. Mandatory monitoring of the concentration of the drug in the blood is carried out with the determination of a safe range, unknown metabolites are detected. Side effects are recorded, the functional state of organs, biochemical and hematological parameters are examined. Prior to the start of the test, a thorough clinical and laboratory examination of volunteers is carried out to exclude acute and chronic diseases. If it is impossible to test the drug on healthy people (for example, cytotoxic drugs, 1C against AIDS), studies are carried out on patients.

Phase II is the key one, since the data obtained determine the feasibility of continuing the study of a new drug in a larger number of patients. Its purpose is to prove the clinical efficacy of J1C when tested on a specific group of patients, to establish the optimal dosing regimen, to further study the safety of the drug in a large number of patients, as well as to study drug interactions. Compare the efficacy and safety of the study drug with the reference and placebo. This phase usually lasts about 2 years.

Phase III - full-scale, expanded multicenter clinical trials of the drug in comparison with placebo or reference drugs. Usually, several controlled studies are carried out in different countries according to a single protocol for clinical trials. The information obtained clarifies the effectiveness of the drug in patients, taking into account concomitant diseases, age, gender, drug interactions, as well as indications for use and dosing regimen. If necessary, pharmacokinetic parameters are studied in various pathological conditions (if they have not been studied in phase II). After the completion of this phase, the pharmacological agent acquires the status of a drug after passing registration (a process of successive expert and administrative-legal actions) with entry into the State Register and assignment of a registration number to it. The documents required for the registration of a new drug are reviewed by the Department of State Control of Medicines and Medical Equipment and sent for examination to the specialized commissions of the Pharmacological and Pharmacopeial Committees. The commissions may recommend that the manufacturer conduct additional clinical studies, including bioequivalence (for generic drugs). With a positive expert assessment of the submitted documents, the commissions recommend that the Department register the drug, after which the drug enters the pharmaceutical market.

Phase IV and post-marketing research. The purpose of phase IV is to clarify the features of the action of drugs, an additional assessment of its effectiveness and safety in a large number of patients. Extended post-registration clinical trials are characterized by the widespread use of a new drug in medical practice. Their purpose is to identify previously unknown, especially rare side effects. The data obtained can serve as the basis for making appropriate changes to the instructions for use of the drug.

evidence-based medicine

The concept of evidence-based medicine, or evidence-based medicine, proposed in the early 1990s, implies the conscientious, accurate and meaningful use of the best results of clinical trials to select the treatment of a particular patient. This approach reduces the number of medical errors, facilitates the decision-making process for practitioners, hospital administrations and lawyers, and reduces healthcare costs. The concept of evidence-based medicine offers methods for correctly extrapolating data from randomized clinical trials to address practical issues related to the treatment of a particular patient. At the same time, evidence-based medicine is a concept or method of decision-making; it does not claim that its conclusions fully determine the choice of drugs and other aspects of medical work.

Evidence-based medicine is designed to address the following important questions:

Can you trust the results of a clinical trial?

What are these results, how important are they?

Can these results be used to make decisions in the treatment of specific patients?

Levels (classes) of evidence. A convenient mechanism that allows a specialist to evaluate the quality of any clinical trial and the reliability of the data obtained is the rating system for evaluating clinical trials proposed in the early 1990s. Usually, from 3 to 7 levels of evidence are distinguished, while with an increase in the ordinal number of the level, the quality of the clinical trial decreases, and the results seem less reliable or have only indicative value. Recommendations from studies at various levels are usually denoted in Latin letters A, B, C, D.

Level I (A) - well-designed, large, randomized, double-blind, placebo-controlled studies. It is customary to refer to the same level of evidence data obtained as a result of a meta-analysis of several randomized controlled trials.

Level II (B) - small randomized and controlled trials (if statistically correct results are not obtained due to the small number of patients included in the study).

Level III (C) - case-control or cohort studies (sometimes referred to as level II).

Level IV (D) - information contained in the reports of expert groups or consensus of specialists (sometimes referred to as level III).

"Endpoints" in clinical trials. Primary, secondary, and tertiary “endpoints” can be used to evaluate the effectiveness of the new J1C in clinical trials. These primary outcomes are assessed in controlled comparative studies of treatment outcomes in at least two groups: the main group (patients receiving a new treatment or new drug) and the comparison group (patients not receiving the study drug or taking a known comparator drug). For example, in the study of the effectiveness of the treatment and prevention of coronary heart disease (CHD), the following "end points" are distinguished.

Primary - the main indicators associated with the possibility of increasing the life expectancy of the patient. In clinical studies, these include a reduction in overall mortality, mortality from cardiovascular diseases, in particular myocardial infarction and stroke.

Secondary indicators - reflect an improvement in the quality of life, either due to a decrease in morbidity or relief of symptoms of the disease (for example, a decrease in the frequency of angina attacks, an increase in exercise tolerance).

Tertiary - indicators associated with the possibility of preventing the disease (for example, in patients with coronary artery disease - stabilization of blood pressure, normalization of blood glucose, a decrease in the concentration of total cholesterol, LDL, etc.).

Meta-analysis is a method of searching, evaluating and combining the results of several controlled studies. As a result of meta-analysis, it is possible to establish positive or undesirable effects of treatment that cannot be identified in individual clinical studies. It is necessary that the studies included in the meta-analysis be carefully randomized, their results published with a detailed study protocol, indication of selection and evaluation criteria, and selection of endpoints. For example, two meta-analyses found a beneficial effect of lidocaine on arrhythmia in patients with myocardial infarction, and one found an increase in the number of deaths, which is the most important indicator for evaluating the effect of this drug.

The value of evidence-based medicine in clinical practice. Currently, the concept of evidence-based medicine is widely used when deciding on the choice of drugs in specific clinical situations. Modern guidelines for clinical practice, offering certain recommendations, provide them with a rating of evidence. There is also an international Cochrane initiative (Cochran Library), which unites and systematizes all the information accumulated in this area. When choosing a drug, along with the recommendations of the drug formulary, international or national clinical practice guidelines are used, that is, systematically developed documents designed to facilitate the practitioner, lawyer and patient in making decisions in certain clinical situations. However, studies conducted in the UK have shown that general practitioners are not always inclined to apply national recommendations in their work. In addition, the creation of clear systems of recommendations is criticized by experts who believe that their use limits the freedom of clinical thinking. On the other hand, the use of such guidelines stimulated the abandonment of routine and insufficiently effective methods of diagnosis and treatment, and ultimately increased the level of medical care for patients.

In conclusion, it should be noted that the results of modern clinical studies cannot be considered definitive and absolutely reliable. Obviously, evolutionary leaps in the study of new drugs have occurred and will continue to occur, which leads and will lead to fundamentally new clinical and pharmacological concepts, and hence to new methodological approaches to the study of drugs in clinical trials.

BASICS RATIONAL PHARMACOTHERAPY

Pharmacotherapy is one of the main methods of conservative treatment. Modern pharmacotherapy is a rapidly developing area of clinical medicine and is developing a scientific system for the use of drugs. Pharmacotherapy is based mainly on clinical diagnostics and clinical pharmacology. The scientific principles of modern pharmacotherapy are formed on the basis of pharmacology, pathological physiology, biochemistry, as well as clinical disciplines. The dynamics of the symptoms of the disease in the course of pharmacotherapy can be a criterion for clinical assessment of the quality and degree of the achieved pharmacological effect.

Basic principles of pharmacotherapy

Pharmacotherapy should be effective, i.e., provide a successful solution of the set goals of treatment in certain clinical situations. The strategic goals of pharmacotherapy can be different: cure (in the traditional sense), slow down the development or relief of exacerbation, prevent the development of the disease (and its complications), or eliminate painful or prognostically unfavorable symptoms. In chronic diseases, medical science has identified the main goal of treating patients with disease control with a good quality of life (i.e. subjectively good condition of the patient, physical mobility, absence of pain and discomfort, ability to serve oneself, social activity).

One of the main principles of modern pharmacotherapy, carried out by highly active drugs acting on various body functions, is the safety of treatment.

The principle of minimizing pharmacotherapy involves the use of a minimum amount of drugs to achieve a therapeutic effect, i.e. limiting pharmacotherapy only to the amount and duration of drug use, without which treatment is either impossible (not effective enough), or requires the use of more “dangerous” methods than pharmacotherapy treatment. This principle implies the rejection of unreasonable polypharmacy and polytherapy. The implementation of this principle is facilitated by a correct assessment of the possibility of partial replacement of pharmacotherapy with other methods of treatment (for example, balneo-, climate-, psycho-, physiotherapy, etc.).

The principle of rationality implies the optimal ratio of efficacy and safety of pharmacotherapy, which ensures the maximum possible therapeutic effect with the lowest risk of developing undesirable effects. When indications for the combined use of several drugs, the principle of rationality involves a medical assessment of the comparative significance of efficacy and safety in order to limit the number of prescribed drugs. Possible contraindications to pharmacotherapy are also assessed, including lack of diagnosis (eg, abdominal pain) and incompatibility of drug and non-drug treatments (eg, defibrillation for cardiac arrhythmia after prior use of cardiac glycosides). In some cases, the ambiguity of the diagnosis, on the contrary, may be an indication for pharmacotherapy for the diagnosis of exjuvantibus. The principle of economical pharmacotherapy is used in cases where the possibility of etiotropic or pathogenetic therapy excludes (or minimizes) the need for the use of symptomatic agents or drugs that act on secondary links of pathogenesis.

The controllability of pharmacotherapy provides for continuous medical analysis and evaluation of both expected and unforeseen results of drug use. This allows you to make timely adjustments to the chosen treatment tactics (changing the dose, route of drug administration, replacing a drug that is ineffective and / or caused side effects with another, etc.). Compliance with this principle is based on the use of objective criteria and methods for assessing the quality and degree of the therapeutic effect, as well as early detection of unwanted and side effects of drugs. The principle of individualization of pharmacotherapy is not always feasible, therefore, the development of scientific prerequisites for its approval is one of the main tasks of clinical pharmacology. The practical implementation of the principle of individualization of pharmacotherapy characterizes the highest level of mastery of the method of pharmacotherapy. It depends on the qualifications of the specialist, providing him with complete and reliable information about the action of the drug, as well as the availability of modern methods for monitoring the functional state of organs and systems, as well as the action of the drug.

Types of pharmacotherapy

There are the following types of pharmacotherapy:

1. Etiotropic (elimination of the cause of the disease).

2. Pathogenetic (influencing the mechanism of the development of the disease).

3. Substitutive (compensation for a lack of vital substances in the body).

4. Symptomatic (elimination of individual syndromes or symptoms of the disease).

5. Restorative (restoration of broken parts of the body's adaptive system).

6. Preventive (prevention of the development of an acute process or exacerbation of a chronic one).

In an acute disease, treatment most often begins with etiotropic or pathogenetic pharmacotherapy. In exacerbation of chronic diseases, the choice of the type of pharmacotherapy depends on the nature, severity and localization of the pathological process, the age and gender of the patient, the state of his compensatory systems, in most cases, treatment includes all types of pharmacotherapy.

The successes of pharmacotherapy in recent years are closely related to the development of the principles and technologies of evidence-based medicine (see the chapter "Clinical drug trials. Evidence-based medicine"). The results of these studies (level of evidence A) contribute to the introduction into clinical practice of new technologies aimed at slowing down the development of the disease and delaying severe and fatal complications (for example, the use of β-blockers and spironolactone in chronic heart failure, inhaled glucocorticoids in bronchial asthma, ACE inhibitors in diabetes, etc.). The evidence-based indications for long-term and even lifelong use of drugs were also expanded.

The relationship between clinical pharmacology and pharmacotherapy is so close that it is sometimes difficult to draw a line between them. Both are based on general principles, have common goals and objectives, namely: effective, competent, safe, rational, individualized and economical therapy. The difference is that pharmacotherapy determines the strategy and goal of treatment, while clinical pharmacology provides tactics and technology to achieve this goal.

Goals and objectives of rational pharmacotherapy

Rational pharmacotherapy of a particular patient includes the following tasks:

Definition of indications for pharmacotherapy and its purpose;

Choice of drugs or combinations of drugs;

The choice of routes and methods of administration, as well as forms of release of drugs;

Determination of the individual dose and dosing regimen of drugs;

Correction of drug dosing regimens during treatment;

Selection of criteria, methods, means and timing of pharmacotherapy control;

Justification of the timing and duration of pharmacotherapy;

Determination of indications and technology of drug withdrawal.

What is the starting point for pharmacotherapy?

Before starting pharmacotherapy, the need for it should be determined.

If intervention during the disease is necessary, the drug can be prescribed provided that the likelihood of its therapeutic effect is greater than the likelihood of undesirable consequences of its use.

Pharmacotherapy is not indicated if the disease does not change the quality of life of the patient, its predicted outcome does not depend on the use of drugs, and also if non-drug methods of treatment are effective and safe, more preferable or inevitable (for example, the need for emergency surgery).

The principle of rationality underlies the construction of pharmacotherapy tactics in a specific clinical situation, the analysis of which makes it possible to justify the choice of the most adequate drugs, their dosage forms, doses and routes of administration, and (presumably) the duration of use. The latter depends on the expected course of the disease, the pharmacological effect, the likelihood of drug dependence.

The goals and objectives of pharmacotherapy largely depend on its type and may differ in etiotropic and pathogenetic treatment.

For example, the goal and task of symptomatic pharmacotherapy in an acute situation are usually the same - easing painful symptoms, pain relief, lowering body temperature, etc.

In pathogenetic therapy, depending on the course of the disease (acute, subacute or chronic), the tasks of pharmacotherapy can vary significantly and determine different technologies for the use of drugs. Thus, the task of pharmacotherapy in hypertensive crisis is to quickly relieve its symptoms and reduce the likelihood of complications under the control of clinical symptoms and reduce blood pressure to the required levels. Therefore, drugs or a combination of drugs are used in the "pharmacological test" technology (see below). With severe and persistent arterial hypertension, a stepwise decrease in blood pressure can be carried out, and the immediate goal of pathogenetic therapy will be to eliminate the symptoms of the disease, and the strategic goal will be to prolong the life of the patient, ensure quality of life, and reduce the risk of complications. During pathogenetic therapy, various technologies are used to provide individualized pharmacotherapy.

Stages of rational pharmacotherapy

The tasks of pharmacotherapy are solved in several stages.

At the first stage, the choice of drugs is usually carried out according to the underlying disease (syndrome). This stage includes determining the goals and objectives of treating a particular patient, taking into account the nature and severity of the disease, the general principles of its treatment, and possible complications of previous therapy. Take into account the prognosis of the disease and the features of its manifestation in a particular patient. It is very important for the effectiveness and safety of pharmacotherapy to determine the degree of functional disorders in the body and the desired level of their recovery.

For example, in a hypertensive crisis in a patient with previously normal blood pressure values, the desired effect is the normalization of blood pressure within 30-60 minutes, and in a patient with stable arterial hypertension, a decrease in blood pressure to the levels to which he is adapted. When removing a patient from acute pulmonary edema, the task of achieving the necessary diuretic effect (1 liter of urine for 1 hour) can be set.

In the treatment of subacute and chronic diseases, the desired result may be different at different stages of therapy.

It is more difficult to choose control parameters during the "metabolic" type of therapy. In these cases, the evaluation of the action of drugs can be carried out indirectly using evidence-based medicine or meta-analysis techniques. For example, in order to prove the effectiveness of trimetazidine in the treatment of coronary artery disease, it was necessary to conduct a multicenter prospective study and evaluate the feasibility of prescribing it, showing a decrease in the incidence of coronary artery disease complications in the study group compared to the control group.

At the first stage, based on the characteristics of the course of the disease (syndrome) and the degree of functional disorders, the main pathophysiological links, the intended targets and mechanisms of drug action, i.e. the spectrum of necessary pharmacodynamic effects of drugs in a particular patient, are determined. Also, the desired (or necessary) pharmacokinetic parameters of the drug and the required dosage form are determined. Thus, a model of the optimal drug for a particular patient is obtained.

The second stage includes the selection of a pharmacological group or groups of drugs, taking into account their mechanism of action and pharmacological properties. The choice of a specific drug depends on its mechanism of action, bioavailability, distribution in tissues and elimination, as well as the availability of the required dosage forms.

The third stage is the choice of a specific drug, determining its dose, frequency of administration and methods for monitoring its effectiveness and safety. The selected drug should correspond to the "optimal" (or approach it).

The fourth stage is a correction in ongoing pharmacotherapy due to its ineffectiveness, the appearance of new symptoms or complications of the disease, or the achievement of a predictable stabilization of the patient's clinical condition.

If therapy is ineffective, it is necessary to prescribe drugs with a different mechanism of action or combinations of drugs. It is necessary to predict and detect a decrease in the effect of some drugs due to tachyphylaxis, induction of liver enzymes, the formation of AT to drugs, etc. doses (for example, clonidine), the appointment of another drug or combination of drugs.

When the patient's condition stabilizes, either the drug should be canceled or it should be prescribed as maintenance therapy. With the abolition of certain drugs (for example, antidepressants, anticonvulsants, clonidine, methyldopa, p-blockers, slow calcium channel blockers, histamine H 2 receptor blockers, systemic glucocorticoids), the dose should be reduced gradually.

Pharmacological history

At the 2nd and 3rd stages of pharmacotherapy, a carefully and purposefully collected pharmacological history is essential for decision making. The information obtained makes it possible to avoid mistakes (sometimes irreparable) in the presence of drug intolerance, to get an idea of the effectiveness or inefficiency of previously used drugs (and sometimes about the reason for low efficiency or developed adverse reactions). For example, adverse drug reactions characteristic of an overdose of theophylline (nausea, vomiting, dizziness, anxiety), when a patient used teopak at a dose of 300 mg, were caused by the fact that the patient carefully chewed the tablets and washed them down with water, which changed the kinetics of the prolonged form of the drug and led to to create a high peak concentration of theophylline in the blood.

Pharmacological history can have a significant impact on the choice of the primary drug or its initial dose, change the tactics of drug therapy. For example, the lack of effect of enalapril 5 mg in the past on arterial hypertension in a patient with type 2 diabetes mellitus suggests the need for a higher dose of the drug. The mention of the “escape” of the diuretic effect of furosemide during long-term use in a patient with chronic heart failure determines the advisability of additionally prescribing a potassium-sparing diuretic or potassium preparations. The ineffectiveness of inhaled glucocorticoids in a patient with bronchial asthma may be the result of a violation of the inhalation technique.

Choice of drug and dosage regimen

In recent years, treatment often begins with regulated drugs. Regulated drugs of first choice for many common diseases are well known and generally prescribed. The drug of first choice is included in the state list of vital drugs, is available in the formulary of the medical institution and is offered in approved standard treatment regimens for the category of patients under consideration. For example, if the “optimal” drug determined by the doctor approaches the regulated drug in terms of pharmacodynamic and pharmacokinetic parameters, the latter may become the drug of first choice.

The 3rd stage of pharmacotherapy is complicated, there are different options for solving its problems. So, when a history of intolerance or a significant lack of effect is indicated when using a regulated drug, another drug is chosen that corresponds to the “optimal” one. It may also be a regulated drug, but in a particular clinical situation it may be necessary to choose a non-standard drug.

After choosing a drug, it is necessary to clarify information about the onset and time of development of its maximum effect, all pharmacological effects, and be sure to correlate the risk of developing undesirable effects with concomitant diseases in a particular patient. After that, already at this stage, sometimes it is necessary to abandon the use of the selected drug. For example, if there are all indications for the use of nitrates in a patient, they are not prescribed for concomitant glaucoma or increased intracranial pressure.

Treatment usually begins with a regulated average dose and the recommended regimen for taking the drug (taking into account the route of administration). When determining the individual dose of the drug, they proceed from the idea of its average dose, i.e., the dose that provides therapeutic drug concentrations in the body with the chosen route of administration in most patients. The individual dose is defined as the deviation from the average required for a particular case. The need to reduce the dose arises in connection with age-related changes, in violation of the functions of organs involved in the elimination of drugs, homeostasis disorders, changes in the sensitivity of receptors in target organs, individual hypersensitivity, etc.

The drug in doses exceeding the average is prescribed with a decrease in the bioavailability of the drug, low sensitivity of the patient to it, as well as the use of drugs that weaken its effects (antagonists or accelerate biotransformation or excretion). An individual dose of a drug may differ significantly from that indicated in reference books and guidelines. In the process of using drugs, the dose is adjusted.

Taking into account the purpose and depending on the duration of the action of the administered drug, a single, daily, and sometimes course dose is determined. Doses of drugs that are characterized by material or functional cumulation may be different at the beginning of treatment (initial, saturating dose) and during its continuation (maintenance dose). For such drugs (for example, cardiac glycosides, amiodarone), various initial dosing regimens are being developed, providing for a different rate of onset of the effect depending on the rate of saturation. When determining a single dose, the criterion for its adequacy is the required therapeutic effect in the expected duration of the drug after its single administration.

An individual drug dosing regimen should be developed in accordance with chronopharmacology, which increases the effectiveness and safety of pharmacotherapy. Chronopharmacological technology that increases the effectiveness of pharmacotherapy is preventive chronotherapy, which takes into account the time of onset of the maximum deviation of a particular function from normal values and the pharmacokinetics of the corresponding drugs. For example, the appointment of enalapril to a patient with arterial hypertension 3-4 hours before the "usual" maximum increase in blood pressure will increase the effectiveness of antihypertensive therapy. A chronopharmacological approach that takes into account biological rhythms underlies the administration of the entire daily dose of systemic glucocorticoids in the morning to reduce the risk of secondary adrenal insufficiency.

The dosing regimen of drugs can be standard, corresponding to the instructions for use. Correction of the dosing regimen is carried out with the peculiarities of the course of the disease, as well as in accordance with the results of the pharmacological test. In some cases, dose titration is used, i.e., a slow, stepwise increase in an individual tolerated dose with strict objective control of predicted adverse reactions and pharmacodynamic effects (for example, dose selection of a p-blocker in chronic heart failure).

The concept of a pharmacological test

A drug test, or pharmacological test, is an assessment of the patient's individual response to the first use of drugs. This is an important technological technique used in pharmacotherapy to individualize treatment. The test allows you to determine the degree and reversibility of functional disorders, the tolerance of the selected drug and, in many cases, predict the clinical effect, as well as determine the dosing regimen (especially if there is a correlation between the first effect of the drug and its subsequent effect).

Pharmacological tests are used in functional diagnostics, for example, stress echocardiography with dobutamine - to verify the diagnosis of coronary artery disease and study the state of viable myocardium in patients with chronic heart failure, echocardiography with a nitroglycerin test - to identify the reversibility of restrictive diastolic dysfunction of the left ventricle; ECG with atropine test - for the differential diagnosis of bradycardia of functional or organic origin; function of external respiration (RF) with a test with p 2 -agonist - to detect the reversibility of bronchial obstruction.

The use of drugs in an acute clinical situation can also be considered a pharmacological test (the doctor evaluates the effectiveness and safety of drugs). For example, with intravenous administration of furosemide, it is necessary to control not only the amount of urine excreted, but also blood pressure due to the risk of developing severe arterial hypotension.

Conducting a test includes dynamic monitoring of indicators that reflect the functional state of the system, which is affected by the selected drug. The study is first carried out at rest before meals (it is possible with physical or other exertion), and then after taking the drug. The duration of the study is determined by the pharmacodynamic, pharmacokinetic properties of the drug and the patient's condition.

A pharmacological test is carried out with drugs that are characterized by the effect of the "first dose" and / or the relationship between blood concentration and potency. The test is ineffective when using JIC with a long latent period for the development of the effect.

When conducting a pharmacological test, it is necessary to choose objective and accessible control methods that correspond to the objectives of the study.

Efficacy and safety control during pharmacotherapy

In order to choose objective and affordable control methods and determine the frequency of their implementation during course pharmacotherapy, it is necessary to answer the following questions.

What are the criteria characterizing the stabilization of the condition in this patient?

What are the parameters whose dynamics reflects the efficacy and safety of the selected drug?

How long after taking the drug should we expect changes in the controlled parameters?

When can the maximum therapeutic effect be expected?

When can stabilization of clinical indicators occur?

What are the criteria for dose reduction or discontinuation of the medicinal product due to the clinical effect obtained?

Changes in what indicators may indicate the "escape" of the effect of the therapy?

The dynamics of what parameters reflects the possibility of side effects of the drug used?

After what period of time after taking the drug is it possible to develop the predicted side effects and what aggravates their manifestation?

The answers to the questions posed should be contained in the program of pharmacotherapy for each patient. It includes mandatory and optional research methods, determination of their frequency and sequence, application algorithm.

In some cases, continuous monitoring of changes in key indicators during drug therapy is absolutely necessary, and the inability to conduct it may

serve as a contraindication to the appointment of drugs (for example, an antiarrhythmic drug for complex cardiac arrhythmias in the absence of ECG monitoring methods).

When conducting drug therapy for chronic diseases, even if the patient receives only preventive therapy and is in remission, the examination should be carried out at least once every 3 months.

Particular attention is paid to the dosing regimen during long-term therapy with drugs with a small therapeutic latitude. Only drug monitoring can avoid severe adverse reactions.

Clinical criteria for the effectiveness of the drug can serve as the dynamics of the patient's subjective sensations (for example, pain, itching, thirst, sleep quality, shortness of breath) and objective signs of the disease. The definition of objective criteria is desirable even when using drugs, the effect of which is assessed mainly subjectively (for example, analgesics, antidepressants). Reduction of any symptom of the disease may be accompanied by an increase in the patient's functionality (for example, an increase in the range of motion in the affected joint after taking an analgesic, a change in behavior after the use of antidepressants), which can be detected using objective tests.

Patient adherence to treatment

The patient's adherence to treatment, or compliance (from the English compliance - consent), implies the conscious participation of the patient in the selection and self-control of pharmacotherapy. The main factors that adversely affect patient adherence to treatment are as follows:

Misunderstanding of the patient's instructions given by the doctor;

Low level of education of the patient;

Elderly age;

mental illness;

Complex scheme for taking drugs;

Appointment of a large number of drugs at the same time;

Lack of patient confidence in the doctor;

Irregular visits to the doctor;

Patients do not understand the severity of their condition;

Memory disorders;

Improving the patient's well-being (may prematurely stop treatment or change the drug regimen);

Development of unwanted drug reactions;

Distorted information about drugs received at the pharmacy, from relatives, acquaintances;

Poor financial situation of the patient. Unsatisfactory patient adherence to treatment (for example, unauthorized drug withdrawal) can lead to unwanted drug reactions, up to severe, life-threatening complications. No less dangerous is the unauthorized change in the dosing regimen of JIC, as well as the independent inclusion of other drugs in the treatment regimen.

What should the doctor do to improve the patient's adherence to treatment?

Clearly name LS.

Clearly explain the purpose of taking drugs.

Indicate the expected time of the expected effect.

Give instructions in case of missing the next drug intake.

Inform about the duration of treatment.

Explain what adverse drug reactions may develop.

Caution if JIC affects physical and mental activity.

Indicate the possible interaction of drugs with alcohol, food, smoking.

Elderly patients and those with memory impairment should be given written instructions about the entire pharmacotherapy regimen. The same category of patients can be recommended to place drugs in advance in containers (jars, boxes, paper or plastic bags, etc.) with the indicated time of admission. Promising areas for increasing patient adherence to treatment are the development of educational programs for patients with bronchial asthma, diabetes mellitus, peptic ulcer and other diseases. Self-monitoring of treatment using individual monitoring devices (peak flow meters, glucometers, blood pressure, heart rate monitoring devices, etc.) contributes to timely self-correction of treatment and timely access to a doctor. The analysis of the treatment control diaries submitted to the patient contributes to the improvement of the quality of individualized therapy.

Pharmacotherapy of emergency conditions

Of particular difficulty for the doctor is the pharmacotherapy of emergency conditions, when the patient may develop paradoxical reactions to administered drugs and increase the risk of their side effects. In emergency conditions, the doctor needs promptness in choosing a drug and using it in adequate doses, taking into account possible drug interactions.

The choice of drug and its dose depends on the specific clinical situation and the dynamics of the main functional indicators of the patient. Thus, the goal of pharmacotherapy for acute pulmonary edema is the rapid elimination of left ventricular overload; depending on the severity of the patient's condition, the pathogenesis of edema, central and peripheral hemodynamics, drugs with various pharmacodynamic effects can be used: drugs with a positive inotropic effect, vasodilators that reduce preload (nitrates, enalapril), antiarrhythmic drugs, diuretics, or a combination of these drugs. The selected drug should be water-soluble, have a short T]/2, be produced in ampoules.

Long-term pharmacotherapy

With long-term pharmacotherapy, a change in the patient's condition can be associated both with the course of the disease and with the ongoing pharmacotherapy. When it is carried out, the following situations may occur.

An increase in the concentration of drugs in the blood due to changes in its pharmacokinetic parameters and / or accumulation of active metabolites. This causes an increase in the pharmacological effect and increases the likelihood of side effects. In this case, the dose of the drug should be reduced or it should be canceled.

Restoration of disturbances in the regulation of body functions, increased compensatory reactions, which can enhance the pharmacological effect at the same concentration of drugs in the blood. And in this case, you should reduce the dose of drugs or cancel it.

A decrease in the clinical efficacy of a drug, associated either with a decrease in its concentration in the blood, or, for example, with a decrease in the sensitivity and / or density of receptors (for example, weakening the effects of β-agonists in bronchial asthma). It is possible to differentiate the cause of the “escape” of the drug effect and choose a therapeutic tactic only after determining its C ss in the blood: if it is reduced, the dose should be increased, and if it corresponds to the therapeutic one, it is necessary to replace the drug with another one with a different mechanism of action.

In some cases, there is a need for long-term (sometimes lifelong) maintenance pharmacotherapy.

If the drug serves as a means of replacement therapy (for example, an insulin preparation for type I diabetes mellitus).

In the formation of a drug-dependent course of the disease with a threat of death when the drug is discontinued (for example, glucocorticoids in the hormone-dependent variant of bronchial asthma).

When correcting persistent functional disorders that significantly affect the quality of life of the patient and the prognosis of the disease (for example, the use of ACE inhibitors in chronic heart failure).

Errors in evaluating the effect of drugs

Errors in assessing the action of the drug are most often associated with the fact that the doctor does not take into account that the developing changes in the patient's condition, expected from the action of the drug, are not always the result of its pharmacological action. They can also be caused by the following factors:

Psychotherapeutic action (similar to the placebo effect);

An effect caused by another drug (for example, the disappearance of ventricular extrasystoles when using an antianginal drug that does not have antiarrhythmic activity);

Spontaneous restoration of impaired function or weakening of the manifestations of the pathological process due to the onset of recovery or the cessation of exposure to pathogenic factors.

An adequate assessment of the relationship between signs of improvement in the patient's condition and the action of drugs allows you to timely cancel unnecessary drugs or replace them with more effective ones.

Timely cancellation of drugs is the last, very important stage of pharmacotherapy. The following justifications for the abolition of drugs or their combinations are possible.

Achieving the goal of pharmacotherapy, i.e. stopping the pathological process or restoring the function, the violation of which served as the basis for prescribing the drug.

Weakening or disappearance of the therapeutic effect, which may be due to the peculiarities of the pharmacological action of the drug or the formation of irreversible changes in target organs.

The predominance of contraindications over indications for the use of drugs as a result of the development of a pathological process or an increase in the risk of dangerous consequences of the drug. (A special case of such justification is the completion of a course of taking drugs with a regulated course dose or duration of use.)

The manifestation of a toxic or side effect of a drug, excluding the possibility of replacing it with a drug of a similar effect (for example, digitalis intoxication is an absolute contraindication to the use of all cardiac glycosides).

Cancellation of drugs is contraindicated if it serves as the only factor in maintaining the vital functions of the body, or if it is canceled, decompensation of functions that ensure the patient's adaptation to the environment is possible.

With indications for drug withdrawal and the absence of contraindications to it, the doctor determines the necessary rate of drug withdrawal, taking into account the changes in the body caused by it. This provision applies primarily to hormonal drugs and drugs that affect neurotransmitter systems (for example, with a sharp abolition of glucocorticoids, adrenal insufficiency may develop, with a sudden abolition of clonidine - severe hypertensive crises).

The following options for canceling drugs are possible, depending on the likelihood of developing a withdrawal syndrome.

Stopping the use of drugs is possible for the vast majority of drugs with their short-term use.

Gradual decrease in the daily dose. The duration of this stage depends on the time required to restore the functional changes caused by the drug (for example, increased sensitivity of adrenoreceptors when taking sympatholytics or suppressed function of the adrenal cortex with long-term use of glucocorticoids).

Cancellation of drugs "under the guise" of another drug that prevents the development of undesirable consequences of withdrawal (for example, the abolition of clonidine against the background of p-blockers or other antihypertensive drugs).

Combined use of drugs

Indications for complex pharmacotherapy can be either the presence of two or more different pathological processes in a patient, each of which requires drug treatment, or a disease in which etiotropic, pathogenetic and / or symptomatic pharmacotherapy is indicated.

The goals of the combined use of drugs are to enhance the therapeutic effect (with insufficient effectiveness of one drug), reduce the dose of the drug to reduce its toxic or undesirable effects, or neutralize the undesirable effect of the main drug (see the chapter "Drug Interactions").

The combined use of drugs is also carried out in accordance with the above general principles of pharmacotherapy based on the results of studying the mechanisms of interaction of drugs, analyzing the pathogenesis of the disease and its manifestations in a particular patient, assessing the degree of functional disorders, the presence of concomitant diseases, the nature of the course of the disease and other factors.

MEDICINAL DRUGS INCREASING VASCULAR TONE

Drugs that increase vascular tone are divided into the following groups.

1. LS central action.

Psychostimulants.

Analeptics.

Tonic drugs.

2. Drugs that stimulate the peripheral nervous system.

Stimulants of a- and (3-adrenergic receptors: epinephrine, ephedrine, dephedrine.

Stimulants predominantly a-adrenergic receptors: norepinephrine, phenylephrine, etaphedrine, midodrine.

Stimulants of dopamine, a- and (3-adrenergic receptors: dopamine.

3. Drug predominantly myotropic action: angiotensinamide. Centrally acting drugs are not considered in this section, since an increase in vascular tone is not considered their main pharmacological effect.