Investigational drug and clinical study materials. Profession: Specialist in clinical drug research. Other toxicity studies

Today, a large number of international clinical drug trials are underway in Russia. What does this give Russian patients, what are the requirements for accredited centers, how to become a participant in the study, and whether its results can be falsified, Tatyana Serebryakova, director of clinical research in Russia and the CIS countries of the international pharmaceutical company MSD (Merck Sharp & Dohme), told MedNovosti.

Tatyana Serebryakova. Photo: from personal archive

What is the path of the drug from the moment of its invention to the receipt in the pharmacy network?

— It all starts with the laboratory, where preclinical studies are carried out. To ensure the safety of a new drug, it is tested on laboratory animals. If any risks, such as teratogenicity (the ability to cause birth defects), are identified during the preclinical study, then such a drug will not be used.

It was the lack of research that led to the terrible consequences of the use of the drug "Thalidomide" in the 50s of the last century. The pregnant women who took it had children with deformities. This is a vivid example, which is given in all textbooks on clinical pharmacology and which prompted the whole world to strengthen control over the introduction of new drugs to the market, made it mandatory to conduct a full-fledged research program.

Clinical research consists of several phases. The first, as a rule, involves healthy volunteers, here the safety of the drug is confirmed. In the second phase, the effectiveness of the drug for the treatment of the disease in a small number of patients is evaluated. In the third, their number is expanding. And if the results of studies show that the drug is effective and safe, it can be registered for use. This is handled by the Ministry of Health.

Drugs developed abroad at the time of filing documents for registration in Russia, as a rule, are already registered in the United States (Food and Drug Administration, FDA) or in Europe (European Medicines Agency, EMA). To register a drug in our country, data from clinical trials conducted in Russia are required.

The production of the drug begins at the research stage - in small quantities - and scales up after registration. Several factories located in different countries can participate in the production of one drug.

Why is it so important that Russians take part in research?

“We are talking specifically about Russian patients suffering from specific diseases; these requirements do not apply to healthy volunteers. It is necessary to make sure that the drug is as safe and effective for Russian patients as it is for participants in studies in other countries. The fact is that the effects of a drug can vary in different populations and regions, depending on various factors (genotype, resistance to treatment, standards of care).

This is especially important when it comes to vaccines. Residents of different countries may have different immunity, so clinical trials in Russia are mandatory to register a new vaccine.

Do the principles of conducting clinical trials in Russia somehow differ from those accepted in world practice?

- All ongoing clinical trials in the world are conducted according to a single international standard called Good Clinical Practice (GCP). In Russia, this standard is included in the GOST system, its requirements are enshrined in legislation. Each international multicenter study is conducted in accordance with the protocol (detailed instructions for conducting the study), which is the same for all countries and is mandatory for all research centers participating in it. Great Britain, and South Africa, and Russia, and China, and the USA can participate in one research. But, thanks to a single protocol, its conditions will be the same for participants from all countries.

Do successful clinical trials guarantee that a new drug is really effective and safe?

- That's why they are held. The study protocol determines, among other things, the statistical methods for processing the information received, the number of patients required to obtain statistically significant results. In addition, the conclusion about the efficacy and safety of the drug is not given on the basis of the results of only one study. As a rule, a whole program of complementary studies is carried out - on different categories of patients, in different age groups.

After registration and use in routine medical practice, monitoring of the efficacy and safety of the drug continues. Even the largest study includes no more than a few thousand patients. And a much larger number of people will take this drug after registration. The manufacturing company continues to collect information about the occurrence of any side effects of the drug, regardless of whether they were registered and included in the instructions for use or not.

Who is authorized to conduct clinical trials?

- When planning a study, the manufacturing company must obtain permission to conduct it in a particular country. In Russia, such a permit is issued by the Ministry of Health. He also maintains a special register of accredited medical institutions for clinical trials. And in each such institution, many requirements must be met - for personnel, equipment, and the experience of research doctors. From among the centers accredited by the Ministry of Health, the manufacturer selects those suitable for his research. The list of centers selected for a particular study also requires approval by the Ministry of Health.

Are there many such centers in Russia? Where are they concentrated?

— Hundreds of accredited centers. This figure is not constant, because someone's accreditation expires, and he can no longer work, and some new centers, on the contrary, join research. There are centers that work only on one disease, there are multidisciplinary ones. There are such centers in different regions of the country.

Who pays for the research?

- The manufacturer of the drug. It acts as the customer of the study and, in accordance with the norms of the law, pays the costs of its conduct to research centers.

And who controls their quality?

— Good Clinical Practice (GCP) assumes that all studies are conducted according to standard rules to ensure quality. Compliance is monitored at different levels. It is the responsibility of the research center itself, by law, to ensure proper quality in research, and this is controlled by the designated principal investigator. The manufacturing company, for its part, monitors the conduct of the study, regularly sending its company representative to the research center. There is a mandatory practice of conducting independent, including international, audits to verify compliance with all requirements of the protocol and GCP standards. In addition, the Ministry of Health also conducts its inspections, monitoring compliance with the requirements of accredited centers. Such a multi-level control system ensures that the information obtained in the study is reliable, and the rights of patients are respected.

Is it possible to falsify research results? For example, in the interests of the customer company?

- The manufacturing company is primarily interested in obtaining a reliable result. If, due to poor-quality research, patients' health deteriorates after using the drug, this may result in litigation and multimillion-dollar fines.

During the research process, a new drug is being tested on humans. How dangerous is it?

"Pregnant Alison Lapper" (sculptor Mark Quinn). Artist Alison Lapper is one of the most famous victims of phocomelia, a birth defect associated with the mother taking thalidomide during pregnancy. Photo: Gaellery/Flickr

“There is always and everywhere danger. But a new drug is being tested in humans when the benefits of treatment outweigh the risks. For many patients, especially those with severe cancer, clinical trials are a chance to gain access to the latest drugs, the best therapy currently available. The studies themselves are organized in such a way as to minimize the risks for participants, first the drug is tested on a small group. There are also strict selection criteria for patients. All participants in the study are provided with special insurance.

Participation in the study is a conscious choice of the patient. The doctor tells him about all the risks and possible benefits of treatment with the investigational drug. And the patient signs a document confirming that he is informed and agrees to participate in the study. Healthy volunteers are also included in the research, receiving a fee for participation. But it must be said that for volunteers, the moral and ethical side, the understanding that by participating in research they help sick people, is of particular importance.

How can a sick person participate in drug research?

- If a patient is treated in a clinic on the basis of which the study is being conducted, then, most likely, he will be offered to become a participant in it. You can also contact such a clinic yourself and find out about the possibility of inclusion in the study. For example, about 30 studies of our new immuno-oncological drug are currently underway in Russia. More than 300 accredited research centers across the country take part in them. We have specially opened a “hot line” (+7 495 916 71 00, ext. 391), through which doctors, patients and their relatives can receive information about the cities and medical institutions where these studies are being conducted, as well as the opportunity to take part in them.

Clinical drug trials, perhaps one of the most mythologized areas of modern pharmacology. It would seem that companies spend years of work and fabulous money to study the effect of a particular drug formula on the human body and put it on sale, but many are still convinced that the matter is unclean and pharmaceutical companies set their own goals exclusively. To dispel the most popular myths and understand the situation, the medical portal "MED-info" spoke with Lyudmila Karpenko, head of the department of medical research and information of one of the leading domestic pharmaceutical companies.

The history of the emergence of the legal framework for clinical trials

In the narrowest sense, evidence-based medicine is a method of medical clinical practice, when a medical practitioner uses only those methods of prevention, diagnosis and treatment in a patient, the usefulness and effectiveness of which has been proven in studies performed at a high methodological level, and provides an extremely low probability of obtaining "accidental results."

Until the middle of the 20th century, in fact, there was no regulatory framework for research, and it arose after several major scandals in the use of understudied drugs. One of the most resonant was the case that resulted in the death of 107 children in 1937, when the M. E. Massengill company used diethylene glycol (a poisonous solvent, which is part of antifreeze for cars). No preclinical or clinical studies have been conducted. As a result, when it became clear that the drug was deadly, it was withdrawn from sale as quickly as possible, but by that time it had managed to claim more than a hundred lives, which prompted the US authorities to pass a law on mandatory drug research before they go on sale.

One of the main reasons that prompted the world community to develop universal rules for conducting clinical trials was the tragedy with thalidomide that occurred in the late 50s and early 60s. During tests on animals, in particular mice, the drug showed its best side and did not reveal any side effects, including in offspring. When the drug was used in pregnant women as a remedy for insomnia and toxicosis, it led to the birth of more than 10,000 children worldwide with defects in tubular bones and limbs. After that, it became obvious that full-fledged tests and studies should be carried out, and the experience of individual specialists cannot be a sufficient basis for registering the drug.

The first laws establishing state control over the production of drugs were adopted in Europe as early as the 1960s. Today, we are guided by the principles of the Declaration of Helsinki of the World Medical Association, which later became the basis for the International Harmonized Tripartite Guideline for Good Clinical Practice (ICH Harmonized Tripartite Guideline for Good Clinical Practice, abbreviated - ICH), which became the basis of local regulations since 1996/97 in the USA , Japan and the EU, and since 2003 introduced by the Order of the Ministry of Health of the Russian Federation No. 266 and in Russia (hereinafter - GOST R 52379-2005 "Good Clinical Practice").

The most common myths about conducting clinical trials:

1. testing new ones in public secretly

Today, when conducting research, we relentlessly follow the letter of the law, that is, the ICH document, according to which patients cannot be exposed to unreasonable risk, their rights and confidentiality of personal information are respected, scientific interest, as well as the interests of society cannot prevail over the safety of patients participating in the study, these studies are evidence-based and verifiable. “Compliance with this standard serves as an assurance to society that the rights, safety and well-being of research subjects are protected, consistent with the principles laid down by the WMA Declaration of Helsinki, and that clinical trial data are reliable.” Few people are protected in this process as much as the patient involved in it. In addition, before any procedure under the study protocol is performed, the patient receives full information about the study, possible risks and inconveniences, procedures and examinations within the study, investigational drugs, the likelihood of falling into one or another treatment group, learns about the presence alternative methods of treatment for their disease, is notified of their unconditional right to refuse to participate in the study at any time without any consequences, and signs an informed consent in the presence of a doctor, which documents the desire of a person to participate in the study. If something is not clear to the patient, the doctor is obliged to give additional explanations on the ongoing study. The patient also has the right to consult about his possible participation in a clinical trial with another specialist who is not part of the research team, or with his relatives and friends.

2. Pharmaceutical companies conduct clinical trials only in developing countries, where costs are lower and legislation is not as strict. For the global pharmaceutical industry, developing countries are a testing ground

First, with regard to the low cost of research in developing countries, this is not a completely correct statement. If we take Russia, which many experts attribute to developing markets, then the cost of conducting clinical trials of medicines in our country approaches and sometimes even exceeds the price level in Europe and the USA, especially when taking into account the current exchange rate. In addition, we have a huge country, which adds to the already impressive amount of costs significant logistics costs, as well as the payment of customs fees and duties, which are levied on drugs and other research materials imported into Russia.

Secondly, research in developing countries requires much more attention and control from companies, which complicates the whole process. Unfortunately, in developing countries there are not always enough qualified medical personnel who can work within the strict framework of the ICH, which requires the companies organizing the study to additionally invest in the training of clinic staff. On the other hand, in such countries, the population often does not have access to the latest medical developments and cannot receive free examination and treatment at the modern level, which is available to patients in developed countries. Therefore, sometimes participation in a clinical trial is the only way to get high-quality high-tech examination and treatment.

Thirdly, regardless of the legislation of a particular country, all studies must comply with the principles and standards of the ICH GCP in order to subsequently have the right to register the drug in the US, EU and other developed countries.

3. Clinical research is not safe for people. And the most dangerous phase I trials, when the drug is first used in humans, are carried out by pharmaceutical companies in developing countries.

First, let's understand the phases of any clinical trial. After preclinical studies and trials of the drug on biological models and animals, the so-called phase I begins - the first human trial, which is generally aimed at assessing the tolerability of the drug by the human body, it involves from several dozen to about 100 people - healthy volunteers. If the drug is highly toxic (for the treatment of oncology, for example), then patients with the corresponding disease take part in the study. As already mentioned, subject to research in developing countries, for many people there, this is the only chance to receive at least some kind of treatment. Phase II involves the participation of several hundred patients suffering from a specific disease, for which the investigational drug is intended to treat. The primary goal of Phase II is to select the most appropriate therapeutic dose of the study drug. And phase III is a pre-registration study involving already several thousand patients, usually from different countries, to obtain reliable statistical data that can confirm the safety and effectiveness of the drug.

Of course, Phase I trials are one of the most dangerous moments of the whole process. That is why they are carried out in specialized institutions, for example, departments of multidisciplinary hospitals specially equipped for such studies, where there is all the necessary equipment and trained medical personnel so that if something goes wrong, they can always respond quickly. Most often, these studies are carried out in the USA, Canada and the Netherlands, and in some countries they are limited or completely prohibited due to their unpredictability, as, for example, in India and Russia (we have a ban imposed on the study of foreign drugs involving healthy volunteers), which makes them impossible or difficult to implement on the territory of these countries.

4. Patients in clinical trials are guinea pigs, no one cares about them.

Few people are as protected in a clinical trial as the patient is. Do not forget that the main principles of research with the participation of people to this day remain voluntary participation and non-harm. All medical manipulations are performed only with the full knowledge of the person and with his consent. This is regulated by the already mentioned Declaration of Helsinki and ICH GCP. The protocol for conducting any clinical trial (and this is the main document), without which the study is impossible and which must be approved and approved by the Ministry of Health, regulates the interaction of the doctor with the patient, including the fact that the doctor provides all the necessary information in full and is responsible for the benefit/risk ratio for the study participant.

All patients participating in a clinical trial are under close medical supervision, regularly undergo various examinations, up to the most expensive ones, at the expense of the company conducting the study; all and any medical events, changes in health status are recorded and studied, with the development of adverse events, even those not related to the investigational drug, they immediately receive adequate treatment. In contrast, patients participating in clinical trials are in better health conditions than others.

The process also involves third-party observers from among the employees of the customer company or contract research organization who control its progress, and if the doctor suddenly violates the established procedure or exceeds his authority, they can initiate severe punishment up to stopping the study.

5. Patients in the control group receive a placebo - a drug - a "dummy", which puts their health and life at risk

It should be remembered that a placebo is an inactive substance that is indistinguishable from the drug under study only by external signs (appearance, taste, etc.), so, in fact, it cannot affect the human body in any way. However, for ethical reasons, the use of placebo in clinical trials is restricted in accordance with the principles of the Declaration of Helsinki. According to them, the benefits, risks, inconveniences, and effectiveness of a new treatment must be weighed against the best available treatments. The exception is when the use of a placebo in a study is justified because there is no effective treatment for the disease, or if there is a compelling evidence-based reason for using a placebo to assess the efficacy or safety of the study treatment. In any case, patients receiving a placebo should not be at risk of causing serious or irreversible harm to health. In addition, a patient participating in a clinical trial is under the close supervision of highly qualified specialists and has access to the most modern drugs and technologies, which makes the risks minimal.

6. Clinical research is overkill. For the release of the drug on the market, information obtained in the course of preclinical trials of the drug on biological models and animals is quite enough.

If that were the case, pharmaceutical companies would have stopped spending billions of dollars on human research long ago. But the thing is that there is no other way to understand how a particular drug affects a person, except to conduct an experiment. It must be understood that the situation modeled in the course of preclinical studies on biological models is, in fact, ideal and far from the real state of affairs. We cannot predict how a particular dose of the drug will affect people with different body weights or with different comorbidities in history. Or how the drug will act on the human body in different dosages, how it will be combined with other drugs. All of this requires research involving humans.

The commercial interests of pharmaceutical companies come into conflict with the need to carefully monitor the progress of clinical trials and obtain reliable scientific data.

Pharmaceutical companies spend billions of dollars on clinical trials for drugs, most of which may never reach the market. In addition, the progress and results of the study are closely monitored by public health authorities, and if they are not completely confident in the quality and reliability of the data obtained, the drug will not be registered, will not enter the market and will not bring profit to the company. So careful control over the study is, first of all, the interest of the customer company.

7. In Russia, many untested drugs are sold in pharmacies, only foreign countries conduct thorough research before bringing drugs to the market

Any clinical trial (CT) is carried out only with the permission of the state authorized body (in the Russian Federation this is the Ministry of Health of the Russian Federation). The decision-making procedure provides for the analysis of documents submitted by the drug development company, including those on conducting clinical trials, by special expert bodies - on the one hand, clinical pharmacologists, and on the other hand, the Ethics Council specially created under the Ministry of Health of the Russian Federation. The fundamental point is precisely the collegiality of decisions and the competence of persons making an independent decision. And just as strictly regulated is the decision-making procedure based on the results of clinical trials, which are considered by experts of the Ministry of Health of the Russian Federation for the completeness and quality of the studies performed, and the achievement of the main goal - to obtain evidence of the effectiveness and safety of using the drug for its intended purpose. It is at this stage that it is decided whether the results obtained are sufficient for registration of the drug or whether additional studies are required. Russian legislation today is not inferior in terms of the level of requirements for conducting and evaluating the results of clinical trials to the regulations of the leading countries of the world.

Post-registration studies. How and for what purposes they are carried out

This is an extremely important stage in the life of any drug, despite the fact that post-registration studies are not required by the regulator. The main goal is to ensure the collection of additional information on the safety and efficacy of the drug on a sufficiently large population for a long time and in "real conditions". The fact is that, in order to ensure a homogeneous sample, clinical trials are conducted, firstly, on a limited population and, secondly, in accordance with strict selection criteria, which usually does not allow, before registration, to assess how the drug will behave in patients with various concomitant diseases, in elderly patients, in patients taking a wide range of other drugs. In addition, given the limited number of patients involved in clinical trials at the stage of pre-registration study of the drug, rare side effects may not be registered simply because they did not occur in this cohort of patients. We will be able to see and identify them only when the drug enters the market and a sufficiently large number of patients receive it.

When a drug is marketed, we must closely monitor its fate in order to assess and study the most important parameters of drug therapy, such as interaction with other drugs, effects on the body with long-term use and in the presence of diseases of other organs and systems, for example, the gastrointestinal tract , history, analysis of the effectiveness of use in people of different ages, identification of rare side effects, and so on. All these data are then entered into the instructions for use of the medicinal product. Also, in the post-registration period, new positive properties of the drug may be discovered, which in the future will require additional clinical studies and may become the basis for expanding the indications for the drug.

If the drug detects previously unknown dangerous side effects, then its use may be limited up to the suspension and withdrawal of registration.

Chapter 3. CLINICAL STUDIES OF DRUGS

Chapter 3. CLINICAL STUDIES OF DRUGS

The emergence of new drugs is preceded by a long cycle of studies, the task of which is to prove the effectiveness and safety of a new drug. The principles of preclinical research in laboratory animals were optimally developed, but in the 1930s it became clear that the results obtained in animal experiments could not be directly transferred to humans.

The first clinical studies in humans were conducted in the early 1930s (1931 - the first randomized blind study of sanocrisin ** 3, 1933 - the first placebo-controlled study in patients with angina pectoris). Currently, several hundred thousand clinical trials (30,000-40,000 per year) have been conducted worldwide. Each new drug is preceded by an average of 80 different studies involving more than 5,000 patients. This significantly lengthens the development period for new drugs (on average 14.9 years) and requires significant costs: manufacturing companies spend an average of $900 million on clinical trials alone. However, only clinical trials guarantee accurate and reliable information about the safety and efficacy of a new drug. drug.

According to the international guidelines for Good Clinical Practice (International Standard for Clinical Research: ICH / GCP), under clinical trial means “a study of the safety and/or efficacy of an investigational product in humans, aimed at identifying or confirming the clinical, desirable pharmacodynamic properties of an investigational product and/or carried out in order to identify its side effects and/or to study its absorption, distribution, biotransformation and excretion” .

Purpose of the clinical trial- obtaining reliable data on the efficacy and safety of the drug, without exposing

while patients (subjects of the study) unreasonable risk. More specifically, the study may aim to study the pharmacological effects of the drug on humans, establish therapeutic (therapeutic) efficacy or confirm efficacy in comparison with other drugs, as well as determine the therapeutic use - the niche that this drug can occupy in modern pharmacotherapy. In addition, a study can be a stage in the preparation of a drug for registration, promote the marketing of an already registered drug, or be a tool for solving scientific problems.

3.1. STANDARDS IN CLINICAL RESEARCH

Before the emergence of uniform standards for clinical trials, patients receiving new drugs were often at serious risk associated with taking insufficiently effective and dangerous drugs. For example, at the beginning of the twentieth century. in a number of countries, heroin was used as a cough medicine; in 1937, in the USA, several dozen children died after taking paracetamol syrup, which included toxic ethylene glycol *; and in the 1960s in Germany and the UK, women who took thalidomide* during pregnancy gave birth to about 10,000 children with severe limb malformations. Incorrect research planning, errors in the analysis of results and outright falsifications caused a number of other humanitarian disasters, which raised the question of legislative protection of the interests of patients participating in research and potential drug users.

Today, the potential risk of prescribing new drugs is significantly lower, since the state authorities that give their approval for their use have the opportunity to evaluate the results of using a new drug in thousands of patients during clinical trials performed according to a single standard.

Currently, all clinical trials are carried out according to a single international standard called GCP. , which was developed by the Drug Control Administration

funds and food products of the US government, WHO and the European Union in the 1980-1990s. The GCP standard regulates the planning and conduct of clinical trials, and also provides for a multi-stage control of patient safety and the accuracy of the data obtained.

The GCP standard takes into account the ethical requirements for conducting research involving humans, formulated by Declaration of Helsinki by the World Medical Association"Recommendations for physicians involved in biomedical research involving humans". In particular, participation in clinical trials can only be voluntary; in the course of the trials, patients should not receive monetary rewards. By signing their consent to become a participant in the study, the patient receives accurate and detailed information about the possible risk to their health. In addition, the patient may withdraw from the study at any time without giving reasons.

Clinical pharmacology, which studies the pharmacokinetics and pharmacodynamics of drugs directly in a sick person, was of great importance in the creation of GCP standards and the entire modern concept of drug clinical trials.

The provisions of the international standard ICH GCP are reflected in Federal Law "On the Circulation of Medicines"(No. 61-FZ dated April 12, 2010) and State Standard "Good Clinical Practice"(GOST R 52379-2005), according to which clinical trials of drugs are carried out in our country. Thus, there is a legal basis for mutual recognition of the results of clinical trials by different countries, as well as for large international clinical trials.

3.2. PLANNING AND CONDUCT OF CLINICAL STUDIES

Planning a clinical trial involves several steps.

Definition of a research question. For example, does drug X actually lower blood pressure significantly in hypertensive patients, or does drug X actually lower blood pressure more effectively than drug Y?

questions, for example: can drug Z reduce mortality in patients with hypertension (main question), how does drug Z affect the frequency of hospitalizations, what is the proportion of patients with moderate hypertension in whom drug Z can reliably control blood pressure (additional questions). The research question reflects the assumption from which the researchers proceed. (research hypothesis); in our example, the hypothesis is that drug Z, having the ability to reduce blood pressure, can reduce the risk of complications associated with hypertension, diseases and, therefore, can reduce the frequency of deaths.

Choice of study design. The study may include several comparison groups (drug A and placebo, or drug A and drug B). Studies in which there is no comparison group do not provide reliable information about the effect of drugs, and at present such studies are practically not carried out.

Determining the sample size. The authors of the protocol must provide for exactly what number of patients will be required to prove the initial hypothesis (the sample size is calculated mathematically based on the laws of statistics). The study can include from a few dozen (in the case when the effect of the drug is significantly pronounced) to 30,000-50,000 patients (if the effect of the drug is less pronounced).

Determining the duration of the study. The duration of the study depends on the time of onset of the effect. For example, bronchodilators improve the condition of patients with bronchial asthma within a few minutes after taking them, and it is possible to register a positive effect of inhaled glucocorticoids in these patients only after a few weeks. In addition, a number of studies require observation of relatively rare events: if an investigational drug is expected to be able to reduce the number of exacerbations of the disease, then long-term follow-up is necessary to confirm this effect. In modern studies, the follow-up period ranges from several hours to 5-7 years.

Selection of the patient population. To get into the study of patients with certain characteristics, the developers create clear criteria. They include age, gender, duration and severity of the disease, the nature of the previous

treatment, concomitant diseases that may affect the assessment of the effect of drugs. Inclusion criteria should ensure the homogeneity of patients. For example, if patients with mild (borderline) hypertension and patients with very high blood pressure are simultaneously included in a hypertension study, the study drug will affect these patients differently, making it difficult to obtain reliable results. In addition, studies usually do not include pregnant women and people with serious illnesses that adversely affect the general condition and prognosis of the patient.

Methods for assessing the effectiveness of treatment. Developers should choose indicators of the effectiveness of the drug, in our example, it should be clarified how exactly the hypotensive effect will be assessed - by a single measurement of blood pressure; by calculating the average daily value of blood pressure; The effectiveness of treatment will be assessed by the impact on the quality of life of the patient or by the ability of drugs to prevent manifestations of complications of hypertension.

Safety assessment methods. Consideration should be given to assessing the safety of treatment and how to register ADRs for investigational products.

The planning stage ends with the writing of the protocol - the main document that provides for the procedure for conducting the study and all research procedures. In this way, study protocol"describes the objectives, methodology, statistical aspects and organization of the study." The protocol is submitted for review to the state regulatory authorities and an independent ethical committee, without the approval of which it is impossible to proceed with the study. Internal (monitoring) and external (audit) control over the conduct of the study evaluates, first of all, the compliance of the investigators' actions with the procedure described in the protocol.

Inclusion of patients in the study- purely voluntary. A prerequisite for inclusion is to familiarize the patient with the possible risks and benefits that he can derive from participating in the study, as well as signing informed consent. ICH GCP rules do not allow the use of material incentives to attract patients to participate in the study (an exception is made for healthy volunteers involved in the study of pharmacokinetics or bioequivalence of drugs). The patient must meet the inclusion/exclusion criteria. Usually

do not allow participation in studies of pregnant women, nursing mothers, patients in whom the pharmacokinetics of the study drug may be changed, patients with alcoholism or drug addiction. Incapacitated patients should not be included in a study without the consent of caregivers, military personnel, prisoners, persons allergic to the investigational drug, or patients who are simultaneously participating in another study. The patient has the right to withdraw from the study at any time without giving reasons.

Study design. Studies in which all patients receive the same treatment are currently practically not carried out due to the low evidence of the results obtained. The most common comparative study in parallel groups (intervention group and control group). A placebo (placebo-controlled study) or other active drug can be used as a control.

Comparative design studies require randomization- allocation of participants to the experimental and control groups randomly, which minimizes bias and bias. The investigator can, in principle, have access to information about which drug the patient is receiving (this may be required if serious adverse reactions occur), but in this case the patient should be excluded from the study.

Individual registration card. An individual registration card is understood as "a printed, optical or electronic document created to record all the information required in the protocol about each subject of the study." On the basis of an individual registration card, a research database is created for statistical processing of the results.

3.3. PHASES OF A CLINICAL DRUG TRIAL

Both the manufacturer and the public are interested in obtaining the most accurate and complete information about the clinical pharmacology, therapeutic efficacy and safety of a new drug in the course of pre-registration studies. Training

registration dossier is impossible without answering these questions. Because of this, the registration of a new drug is preceded by several dozen different studies, and every year both the number of studies and the number of their participants increases, and the total cycle of studies of a new drug usually exceeds 10 years. Thus, the development of new drugs is possible only in large pharmaceutical companies, and the total cost of a research project on average exceeds $900 million.

The first, preclinical studies begin shortly after the synthesis of a new, potentially effective molecule. Their essence is to test the hypothesis about the proposed pharmacological action of a new compound. In parallel, the toxicity of the compound, its oncogenic and teratogenic effects are being studied. All these studies are performed on laboratory animals, and their total duration is 5-6 years. As a result of this work, out of 5-10 thousand new compounds, approximately 250 are selected.

Actually clinical trials are conditionally divided into four periods or phases.

I phase of clinical trials, usually carried out on 28-30 healthy volunteers. The purpose of this stage is to obtain information about the tolerability, pharmacokinetics and pharmacodynamics of a new drug, clarify the dosing regimen and obtain data on the safety of the drug. The study of the therapeutic effect of the drug in this phase is not necessary, since in healthy volunteers a number of clinically important properties of the new drug are usually not observed.

Phase I studies begin with a study of the safety and pharmacokinetics of a single dose, the choice of which uses data obtained from biological models. In the future, the pharmacokinetics of the drug with repeated administration, the excretion and metabolism of a new drug (the order of kinetic processes), its distribution in fluids, body tissues, and pharmacodynamics are studied. Usually, all these studies are carried out for various doses, dosage forms and routes of administration. During phase I studies, it is also possible to evaluate the effect on the pharmacokinetics and pharmacodynamics of a new drug of other drugs, the functional state of the body, food intake, etc.

An important goal of phase I clinical trials is to identify potential toxicity and ADRs, but these studies are short and are carried out in a limited number of participants, therefore, during this phase, only the most

frequent and severe adverse events associated with the use of a new drug.

In some cases (oncological drugs, drugs for the treatment of HIV infection), phase I studies can be performed in patients. This allows you to speed up the creation of a new drug and not expose volunteers to unreasonable risk, although this approach can be considered rather as an exception.

Phase I studies allow:

Assess the tolerability and safety of a new drug;

In some cases, to get an idea of ​​its pharmacokinetics (in healthy people, which naturally has a limited value);

Determine the main pharmacokinetic constants (C max ,

C1);

Compare the pharmacokinetics of a new drug using different dosage forms, routes and methods of administration.

Phase II studies- the first studies in patients. The volume of these studies is much larger than in phase I: 100-200 patients (sometimes up to 500). In phase II, the efficacy and safety of the new drug, as well as the range of doses for the treatment of patients, are clarified. These studies provide information mainly about the pharmacodynamics of a new drug. Comparative design and the inclusion of a control group (which is not typical for phase I studies) are considered mandatory conditions for conducting phase II studies.

Phase III studies are planned for a large number of patients (up to 10,000 people or more), and the conditions for their implementation are as close as possible to the usual conditions for the treatment of certain diseases. Studies in this phase (usually several parallel or sequential studies) are large (full-scale), randomized and comparative. The subject of study is not only the pharmacodynamics of a new drug, but also its clinical efficacy 1 .

1 For example, the goal of studying a new antihypertensive drug in phases I-II is to prove its ability to reduce blood pressure, and in a phase III study, the goal is to study the effect of drugs on hypertension. In the latter case, along with a decrease in blood pressure, other points for evaluating the effect appear, in particular, a decrease in mortality from cardiovascular diseases, the prevention of complications of hypertension, an increase in the quality of life of patients, etc.

In phase III studies, the drug is compared in terms of efficacy and safety with a placebo (placebo-controlled study) or / and with another marker drug (drug commonly used in this clinical situation and with well-known therapeutic properties).

Submission by the company-developer of an application for registration of drugs does not mean the completion of research. Phase III studies completed prior to application submission are referred to as Phase III studies, and those completed after application submission are referred to as Phase III studies. The latter are carried out to obtain more complete information about the clinical and pharmacoeconomic efficacy of drugs. Such studies can expand the indications for the appointment of a new drug. Additional studies may be initiated by the state authorities responsible for the registration process, if the results of previous studies do not allow us to unambiguously speak about the properties and safety of a new drug.

The results of phase III studies become decisive when deciding on the registration of a new drug. Such a decision may be made if the drug:

More effective than already known drugs of similar action;

Has effects that are not characteristic of existing drugs;

Has a more beneficial dosage form;

More beneficial in pharmacoeconomic terms or allows the use of simpler methods of treatment;

Has advantages when combined with other drugs;

Has an easier way to use.

Phase IV studies. Competition with new drugs forces us to continue research even after the registration of a new drug (post-marketing studies) to confirm the effectiveness of the drug and its place in pharmacotherapy. In addition, phase IV studies allow answering some questions that arise during the use of drugs (the optimal duration of treatment, the advantages and disadvantages of a new drug in comparison with others, including newer drugs, the features of prescribing in the elderly, children, long-term effects of treatment, new indications, etc.).

Sometimes phase IV studies are carried out many years after drug registration. An example of such delayed by more than 60 years

Clinical studies of all phases are carried out in 2 centers (medical centers, hospitals, polyclinics) officially certified by state control bodies, which have the appropriate scientific and diagnostic equipment and the ability to provide qualified medical care to patients with ADR.

Bioequivalence studies. Most drugs on the pharmaceutical market are generic (generic) drugs. The pharmacological action and clinical efficacy of drugs that are part of these drugs, as a rule, are well studied. However, the effectiveness of generics can vary significantly.

Registration of generic drugs can be simplified (in terms of time and volume of studies). To make a strictly justified conclusion about the quality of these funds allow bioequivalence studies. In these studies, the generic drug is compared with the original drug in terms of bioavailability (the proportion of the drug reaching the systemic circulation and the rate at which this process occurs are compared). If two drugs have the same bioavailability, they are bioequivalent. At the same time, it is assumed that bioequivalent drugs have the same efficacy and safety 3 .

Bioequivalence is studied on a small number of healthy volunteers (20-30), while using standard procedures for the study of pharmacokinetics (building a pharmacokinetic curve, studying the value of AUC, T max , C max).

max max

1 Introduced into clinical practice about 100 years ago, these drugs at one time did not go through the process of registration and clinical trials, which required their comprehensive studies after more than 60 years. The modern registration system for new drugs appeared in the 60s of the XX century, therefore, about 30-40% of drugs used today have not been convincingly studied. Their place in pharmacotherapy may be the subject of discussion. In the English-language literature, the term “orphan drugs” is used for these drugs, since it is rarely possible to find funding sources for research on such drugs.

2 In our country - the Ministry of Health and Social Development of the Russian Federation.

3 However, it cannot be argued that two pharmaceutically equivalent drugs (with the same efficacy and safety) always have the same pharmacokinetics and comparable bioavailability.

3.4. ETHICAL ASPECTS OF CLINICAL

RESEARCH

The most important principle of medical ethics was formulated almost 2500 years ago. The Hippocratic Oath says: "I undertake to do all this according to my ability and knowledge for the benefit of the sick person and to abstain from everything that can harm him." The requirements of medical deontology are of particular importance when conducting clinical trials of drugs because they are carried out on people and affect human rights to health and life. Therefore, medico-legal and medico-deontological problems are of great importance in clinical pharmacology.

When conducting clinical trials of drugs (both new and already studied, but used for new indications), one should be guided primarily by the interests of the patient. Permission to conduct clinical trials of drugs is taken by the competent authorities (in the Russian Federation - the Ministry of Health and Social Development of Russia) after a detailed study of the totality of data obtained during the preclinical study of the drug. However, regardless of the permission of the state authorities, the study must also be approved by the ethics committee.

Ethical review of clinical trials is carried out in accordance with the principles of the Declaration of Helsinki of the World Medical Association "Recommendations for physicians involved in biomedical research involving humans" (first adopted by the 18th World Medical Assembly in Helsinki in 1964 and then was repeatedly supplemented and revised).

The Declaration of Helsinki states that the goal of biomedical research in humans should be to improve diagnostic, therapeutic and preventive procedures, as well as to elucidate the etiology and pathogenesis of diseases. The World Medical Assembly has prepared recommendations for the doctor when conducting clinical trials.

The requirements of the Declaration of Helsinki were taken into account in the Federal Law of the Russian Federation "On the Circulation of Medicines". In particular, the following is legally confirmed.

Participation of patients in clinical drug trials can only be voluntary.

The patient gives written consent to participate in clinical trials of drugs.

The patient should be informed about the nature of the study and the possible risk to their health.

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

According to ethical requirements, clinical trials of drugs in relation to minors (with the exception of those cases when the studied drug is intended exclusively for the treatment of childhood diseases) and pregnant women are unacceptable. It is prohibited to conduct clinical trials of drugs in minors without parents, incapacitated persons, prisoners, military personnel, etc. All participants in clinical trials must be insured.

The issues of ethical review of clinical trials in our country are handled by the ethics committee of the Ministry of Health and Social Development of Russia, as well as local ethics committees at medical and scientific medical institutions. The Ethics Committee is guided by the main international principles for conducting clinical trials, as well as the current legislation and regulations of the Russian Federation.

3.5. REGISTRATION PROCEDURE FOR NEW DRUGS

According to the Federal Law "On the Circulation of Medicines" (No. 61-FZ of April 12, 2010), "Medicines can be produced, sold and used on the territory of the Russian Federation if they are registered by the federal drug quality control authority." The following are subject to state registration:

New drugs;

New combinations of previously registered drugs;

Drugs registered earlier, but produced in other dosage forms or in a new dosage;

generic drugs.

The state registration of drugs is carried out by the Ministry of Health and Social Development of Russia, which also approves the instructions for the use of drugs, and the registered drugs are entered in the state register.

Clinical pharmacology and pharmacotherapy: textbook. - 3rd ed., revised. and additional / ed. V. G. Kukes, A. K. Starodubtsev. - 2012. - 840 p.: ill.

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.

Planning and conducting clinical trials of medicines. Protection of the rights of the subjects. Informed consent of the subjects. Ethics committee approval. Mandatory patient insurance. Completed by: Student of group 110 Sannikova A.A.

Planning and conducting clinical trials of drugs. Clinical trials of a drug are a necessary step in the development of any new drug, or expansion of indications for the use of a drug already known to doctors.

At the initial stages of drug development, chemical, physical, biological, microbiological, pharmacological, toxicological and other studies are carried out on tissues (in vitro) or on laboratory animals. These are the so-called preclinical studies, the purpose of which is to obtain, by scientific methods, assessments and evidence of the effectiveness and safety of medicines. However, these studies cannot provide reliable information about how the studied drugs will act in humans, since the body of laboratory animals differs from the human body both in terms of pharmacokinetic characteristics and in the response of organs and systems to drugs. Therefore, it is necessary to conduct clinical trials of drugs in humans.

So, what is a clinical study (test) of a drug? This is a systematic study of a medicinal product through its use in a person (patient or healthy volunteer) in order to assess its safety and efficacy, as well as to identify and confirm its clinical, pharmacological, pharmacodynamic properties, assessment of absorption, distribution, metabolism, excretion and / or interaction with other medicines.

Participants in a Clinical Trial The decision to start a clinical trial is made by the Sponsor/Customer, who is responsible for the organization, control and financing of the trial. The responsibility for the practical conduct of the study rests with the Researcher (a person or group of persons). As a rule, the sponsors are pharmaceutical companies - drug developers, however, the researcher can also act as a sponsor if the study was initiated on his initiative and he bears full responsibility for its conduct.

Clinical trials must be conducted in accordance with the fundamental ethical principles of the Declaration of Helsinki, the Nuremberg Code, GСP (Good Clinical Practice) Rules and applicable regulatory requirements. Prior to the start of a clinical trial, an assessment should be made of the relationship between the foreseeable risk and the expected benefit for the subject and society. At the head is the principle of priority of the rights, safety and health of the subject over the interests of science and society. The subject can be included in the study only on the basis of voluntary informed consent obtained after a detailed acquaintance with the study materials.

The clinical trial must be scientifically justified and described in detail and clearly in the study protocol. Evaluation of the balance of risks and benefits, as well as review and approval of the study protocol and other documentation related to the conduct of clinical trials, are the responsibilities of the Expert Council of the Organization / Independent Ethics Committee (IEC / IEC). Once approved by the IRB/IEC, the clinical trial can proceed.

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 the subjects of the study, as well as methods and timing for evaluating, recording and statistical processing of efficacy and safety indicators.

The objectives of the test must be clearly stated. Regardless of the goal, it is necessary to clearly articulate what end result will be quantified. 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 women, breastfeeding patients, patients with severely impaired liver and kidney function, aggravated by an allergic history are not allowed to participate in studies. Incapacitated patients are not allowed to be included in the study without the consent of the trustees, as well as military personnel and 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. Usually, patients with a certain risk of adverse reactions are excluded from the study, for example, patients with bronchial asthma, etc.

The safety of drugs is assessed throughout the study by analyzing physical data, anamnesis, performing functional tests, ECG, laboratory tests, measuring pharmacokinetic parameters, registering concomitant therapy, as well as 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.

Protection of the rights of the subjects. In any clinical trial, the rights of the subjects must be respected. Rights in Russia are guaranteed by: the Constitution, Federal Law No. 323 “On the Fundamentals of Health Protection in the Russian Federation”, the Helsinki Declaration, the Nuremberg Code and international law,

In the Constitution of the Russian Federation, Art. 21 states: “No one shall be subjected to torture, violence, other cruel or degrading treatment or punishment. No one can be subjected to medical, scientific or other experiments without voluntary consent. » Any study is conducted with the voluntary informed consent of the subjects. This is reflected in Art. 20 Federal Law No. 323 "On the basics of health care in the Russian Federation"

article 20 the risks associated with them, possible options for medical intervention, its consequences, as well as the expected results of medical care.

Informed voluntary consent to medical intervention is given by one of the parents or other legal representative, if the person is not legally capable. A citizen, one of the parents or other legal representative of the person has the right to prevent interference. But in case of refusal in an accessible form, the possible consequences of such a refusal should be explained, and also that the medical organization has the right to go to court to protect the interests of such a person.

Informed voluntary consent to medical intervention or refusal of medical intervention is drawn up in writing, signed by a citizen, one of the parents or other legal representative, a medical worker and is contained in the patient's medical records. Compulsory medical measures may be applied to persons who have committed crimes on the grounds and in the manner established by federal law.

Medical intervention without the consent of a citizen, one of the parents or other legal representative is allowed: 1) if medical intervention is necessary for emergency reasons to eliminate the threat to a person's life and if his condition does not allow him to express his will. 2) in relation to persons suffering from diseases that pose a danger to others; 3) in relation to persons suffering from severe mental disorders; 4) in relation to persons who have committed socially dangerous acts; 5) during the conduct of a forensic medical examination and (or) a forensic psychiatric examination.

Ethics committee approval. “The Ethics Committee is an independent body (institutional, regional, national, or supranational) composed of individuals with and without a scientific/medical background whose responsibilities include protecting the rights, safety, and well-being of research subjects and safeguarding the public this protection through review and approval of the clinical trial protocol, the acceptability of investigators, equipment, and the methods and materials that are intended to be used in obtaining and documenting the informed consent of research subjects.

To conduct a multicenter clinical trial (CT), permission from the Russian Ministry of Health and Social Development is required. But first you need to get the opinion of the expert council and the approval of the ethical committee at the same body, and then the approval of clinical trials in the local ethical committees (LEC) of the selected bases.

CT, the subject of which is related to the use of drugs, methods of diagnostics and treatment in humans, should be checked for compliance with international and Russian legislative acts and ethical principles of biomedical research in humans. When planning a clinical trial involving a person as an object of study, the applicant for a scientific degree must be strictly guided by the normative and regulatory documentation of the Ministry of Health of Russia, as well as obtain written informed consent from the persons participating in the study, or their legal representatives, and approval to conduct the study by an independent LEK. Without compliance with all the above requirements, CT cannot be conducted.

Compulsory patient insurance The contract of compulsory life and health insurance for patients participating in clinical trials of medicinal products protects the property interests of the insured organization and insured persons. The program of compulsory life and health insurance for patients participating in clinical trials of a medicinal product provides protection against the risks associated with the death and deterioration of the health of the insured persons.

The insurer pays 2 million rubles in the event of the death of the insured person as a result of participation in drug trials. Compensation is paid to beneficiaries. The insurance company compensates the insured person for financial losses associated with the deterioration of health, which led to the establishment of disability. The amount of compensation is 1.5 million rubles for group I disability, 1 million rubles for group II disability, and 500,000 rubles for group III disability. The insurer also compensates the patient for losses associated with the deterioration of health, which did not lead to the establishment of disability. In this case, the amount of compensation is up to 300,000 rubles.

The procedure for drawing up an insurance contract for conducting clinical trials. The contract is concluded on the basis of the "Application for insurance". The Application specifies the maximum number of patients (based on which the insurance premium is calculated under the contract), the name of the medicinal product, the objectives of the clinical trial, the name of the clinical trial protocol.

Stages of concluding an insurance contract 1. The parties sign a Confidentiality Agreement (at the request of the Insured). 2. The insured provides the "Clinical Research Protocol" and "Application for Insurance", indicating the maximum number of patients participating in the research. 3. RESO-Garantia prepares a set of documents and sends the electronic version to the Policyholder for approval. 4. The parties sign the insurance contract and exchange original documents. 5. The policyholder pays the insurance premium. 6. The insured provides identification codes of patients (as soon as consent to a clinical trial is obtained). 7. The Guarantee draws up policies for each Insured, patient and researcher leaflets.