Types of clinical trials of drugs. Myths and reality of clinical drug trials Objectives of laboratory research

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 the new drug. The principles of preclinical research in laboratory animals were well established, 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 carried out in the early 1930s (1931 - the first randomized blind study of sanocrysin** 3, 1933 - the first placebo-controlled study in patients with angina pectoris). Currently, several hundred thousand clinical studies have been conducted worldwide (30,000-40,000 per year). The appearance of 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 the receipt of accurate and reliable information about the safety and effectiveness of a new drug. drug.

According to the international guidelines for Good Clinical Practice (international standard for clinical research: ICH/GCP), under clinical trial understand “a study of the safety and/or effectiveness of an investigational drug in humans, aimed at identifying or confirming the clinical, desired pharmacodynamic properties of the investigational drug and/or conducted 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 effectiveness and safety of the drug without exposing

in this case, patients (research subjects) are exposed to unreasonable risks. More specifically, the study may aim to study the pharmacological effect of the drug on humans, establish therapeutic (therapeutic) effectiveness or confirm effectiveness in comparison with other drugs, as well as determine the therapeutic use - the niche that this drug can occupy in modern pharmacotherapy. In addition, research can be a stage in preparing a drug for registration, help promote an already registered drug on the market, or be a tool for solving scientific problems.

3.1. STANDARDS FOR CLINICAL TRIALS

Before the advent of uniform standards for clinical trials, patients receiving new drugs were often exposed to serious risks 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 treatment; 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, approximately 10,000 children were born with severe limb abnormalities to women who took thalidomide* during pregnancy. Incorrect planning of studies, errors in the analysis of results and outright falsifications have caused a number of other humanitarian disasters, which raised the question of legislative protection of the interests of patients participating in studies and potential consumers of drugs.

Today, the potential risk of prescribing new drugs is significantly lower, since government agencies 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 studies are carried out according to a single international standard, called GCP. , which was developed by the Drug Control Administration

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

The GCP standard takes into account the ethical requirements for scientific research involving human subjects, formulated by Declaration of Helsinki of the World Medical Association"Recommendations for Clinicians Conducting Biomedical Research Involving Human Subjects." In particular, participation in clinical trials can only be voluntary; patients should not receive monetary compensation during the research. By signing his consent to become a study participant, the patient receives accurate and detailed information about the possible risk to his health. In addition, the patient can stop participating in the study at any time without giving any reason.

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 clinical trials of drugs.

The provisions of the international standard ICH GCP are reflected in Federal Law “On 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 the mutual recognition of the results of clinical trials between different countries, as well as for the conduct of large international clinical trials.

3.2. PLANNING AND CONDUCTING CLINICAL STUDIES

Planning a clinical trial involves several stages.

Definition of the research question. For example, does drug X significantly reduce blood pressure in patients with hypertension, or does drug X actually lower blood pressure more effectively than drug Y? A study typically has one main study and several additional study arms.

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 is able to reliably control blood pressure levels (additional questions). The research question reflects the assumption from which the researchers start (research hypothesis); in our example, the hypothesis is that drug Z, having the ability to lower blood pressure, can reduce the risk of hypertension-related complications and diseases and, therefore, can reduce the incidence of deaths.

Selecting a study design. The study may include several comparison groups (drug A and placebo or drug A and drug B). Studies that do not have a comparison group do not provide reliable information about the effects of drugs, and at present such studies are practically not carried out.

Determining the sample size. The authors of the protocol must foresee exactly what number of patients will be needed to prove the initial hypothesis (the sample size is calculated mathematically based on the laws of statistics). The study can include from several 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, but it is possible to register the positive effect of inhaled glucocorticoids in these patients only after several weeks. In addition, some studies require observation of relatively rare events: if the study drug is expected to reduce the number of exacerbations of the disease, then long-term follow-up is necessary to confirm this effect. In modern studies, observation periods range from several hours to 5-7 years.

Selection of patient population. To include patients with certain characteristics into the study, 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 the drug. Inclusion criteria should ensure homogeneity of patients. For example, if a hypertension trial were to simultaneously enroll patients with mild (borderline) hypertension and patients with very high blood pressure, the study drug would affect these patients differently, making it difficult to obtain reliable results. In addition, studies usually do not include pregnant women and people with severe diseases that negatively affect the general condition and prognosis of the patient.

Methods for assessing the effectiveness of treatment. Developers must select indicators of the effectiveness of the drug; in our example, it is necessary to clarify how exactly the hypotensive effect will be assessed - by a single measurement of blood pressure; by calculating the average daily blood pressure; the effectiveness of treatment will be assessed by the effect on the patient’s quality of life or by the ability of the drug to prevent the manifestations of complications of hypertension.

Safety assessment methods. Measures should be in place to assess the safety of treatment and methods for recording ADRs of investigational drugs.

The planning stage ends with the writing of a protocol - the main document that provides for the conduct of the study and all research procedures. Thus, research protocol“describes the objectives, methodology, statistical aspects, and organization of the study.” The protocol is provided for review to government regulatory authorities and an independent ethical committee, without whose approval the study cannot begin. Internal (monitoring) and external (audit) control over the study evaluates, first of all, the compliance of the researchers’ actions with the procedure described in the protocol.

Inclusion of patients in the study- purely voluntary. A mandatory condition for inclusion is that the patient is familiarized 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 financial incentives to attract patients to participate in a study (an exception is made for healthy volunteers recruited to study the pharmacokinetics or bioequivalence of drugs). The patient must meet the inclusion/exclusion criteria. Usually

Pregnant women, nursing mothers, patients in whom the pharmacokinetics of the study drug may be altered, and patients with alcoholism or drug addiction are not allowed to participate in studies. It is unacceptable to include incapacitated patients into the study without the consent of caregivers, military personnel, prisoners, persons with an allergy to the study drug, or patients who are simultaneously participating in another study. The patient has the right to stop participating in the study at any time without giving reasons.

Study design. Studies in which all patients receive the same treatment are currently practically non-existent due to the low evidence of the results obtained. The most common comparative study is parallel group (intervention and control group). A placebo (placebo-controlled trial) or another active drug can be used as a control.

Studies with comparative designs require randomization- random distribution of participants into experimental and control groups, which allows to minimize systematic error and bias. The researcher can, in principle, gain access to information about which drug the patient is receiving (this may be necessary if serious adverse reactions occur), but in this case the patient must be excluded from the study.

Individual registration card. An individual registration card is defined as “a printed, optical, or electronic document created to record all protocol-required information about each study subject.” Based on the individual registration card, a research database is created for statistical processing of the results.

3.3. PHASES OF CLINICAL DRUG TRIALS

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 during pre-registration studies. Preparation

registration dossier is impossible without answers to these questions. Because of this, the registration of a new drug is preceded by several dozen different studies, and both the number of studies and the number of their participants increases every year, and the total research cycle 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 soon after the synthesis of a new, potentially effective molecule. Their essence is to test the hypothesis about the expected pharmacological action of a new compound. At the same time, 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, approximately 250 are selected from 5-10 thousand new compounds.

Clinical trials themselves are conventionally divided into four periods or phases.

Phase I 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 the new drug, clarify the dosage regimen and obtain data on the safety of the drug. Studying the therapeutic effect of the drug in this phase is not necessary, since a number of clinically important properties of the new drug are usually not observed in healthy volunteers.

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

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

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

In some cases (oncology drugs, drugs for the treatment of HIV infection), phase I studies can be carried out in patients. This makes it possible to speed up the creation of a new drug and not expose volunteers to unreasonable risks, although this approach can be considered more of an exception.

Phase I studies allow:

Assess the tolerability and safety of a new drug;

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

Determine the main pharmacokinetic constants (Cmax,

C1);

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

Phase II studies- first studies in patients. The volume of these studies is significantly larger than in phase I: 100-200 patients (sometimes up to 500). In phase II, the effectiveness and safety of the new drug, as well as the dosage range for treating patients, are clarified. These studies provide information mainly on the pharmacodynamics of the new drug. Comparative design and inclusion of a control group are considered mandatory conditions for conducting phase II studies (which is not typical for phase I 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 the new drug, but also its clinical effectiveness 1 .

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

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

Submission by the developer of an application for drug registration does not mean the completion of research. Phase III studies performed before filing an application are called phase Ia studies, and those performed after filing an application are called phase III studies. The latter are carried out to obtain more complete information about the clinical and pharmacoeconomic effectiveness of drugs. Such studies may expand the indications for prescribing a new drug. Additional studies may be initiated by government agencies responsible for the registration process if the results of previous studies do not allow an unambiguous statement about the properties and safety of the new drug.

The results of phase III studies become decisive when deciding to register a new drug. This 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 advantageous dosage form;

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

It has advantages when used together with other drugs;

Has an easier way to use.

Phase IV studies. Competition with new drugs forces research to continue even after 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 make it possible to answer 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, features of prescription 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 deferrals of more than 60 years

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

Bioequivalence studies. Most drugs on the pharmaceutical market are reproduced (generic) drugs. The pharmacological action and clinical effectiveness of the drugs included in these drugs, as a rule, have been quite well studied. However, the effectiveness of generics can vary significantly.

Registration of generic drugs can be simplified (in terms of time and scope of research). Bioequivalence studies allow us to make a strictly substantiated conclusion about the quality of these products. 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. It is assumed that bioequivalent drugs have the same effectiveness and safety 3 .

Bioequivalence is studied on a small number of healthy volunteers (20-30), using standard procedures for studying pharmacokinetics (construction of a pharmacokinetic curve, studies of AUC, Tmax, Cmax values).

max max

1 Proposed into clinical practice about 100 years ago, these drugs at one time did not undergo the process of registration and clinical trials, which required their extensive research more than 60 years later. The modern system for registering new drugs appeared in the 60s of the 20th century, therefore, about 30-40% of drugs used today have not been convincingly studied. Their place in pharmacotherapy may be a matter of debate. In the English-language literature, the term “orphan drugs” is used for these drugs, since it is rarely possible to find sources of funding 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 stated 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 states: “I undertake to do all this according to my ability and knowledge for the benefit of the patient and to abstain from everything that can cause him harm.” The requirements of medical deontology acquire particular importance when conducting clinical trials of drugs because they are conducted on people and affect human rights to health and life. Consequently, 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 accepted 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 government approval, the study must also receive approval from an ethics committee.

Ethical review of clinical research is carried out in accordance with the principles of the Declaration of Helsinki of the World Medical Association “Recommendations for physicians engaged in biomedical research involving human subjects” (first adopted by the 18th World Medical Assembly in Helsinki in 1964 and subsequently amended and revised several times).

The Declaration of Helsinki states that the purpose 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 physicians 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 confirmed by law.

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

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

The patient must be informed about the nature of the study and the possible risk to his health.

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

According to ethical requirements, clinical trials of drugs in relation to minors (except for those cases when the drug being studied is intended exclusively for the treatment of childhood diseases) and pregnant women are prohibited. It is prohibited to conduct clinical trials of drugs in minors without parents, incompetent 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 dealt with 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 basic international principles of conducting clinical research, as well as the current legislation and regulations of the Russian Federation.

3.5. PROCEDURE FOR REGISTRATION OF NEW MEDICINES

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

New drugs;

New combinations of previously registered drugs;

Medicines 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, it also approves the instructions for the use of drugs, and the registered drug is entered into the state register.

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

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Clinical studies on humans

Modern medicine is unthinkable without active scientific experiments and research. New medicines and dietary supplements, examination methods, and treatment methods must undergo thorough testing. In this regard, a number of important ethical problems arise, the main one of which, perhaps, is how to combine scientific interests and benefits for a particular subject. Undoubtedly, this problem must be solved based on the Kantian principle: man is not a means, but an end. The experimental physician conducting the research must be guided by the priority of the patient's benefit over public benefit and scientific interests.

Let's give some examples. In 1932, the U.S. Department of Health conducted a study of the natural history of syphilis in 399 African Americans in Tuskegee, Alabama. The study continued until 1972. It was stopped due to a media leak (the study was originally supposed to end when all participants died and autopsies were performed). Some patients by this time died from syphilis, others from complications caused by it.

Introduced into clinical practice in 1935, sulfonamide drugs became the first effective drugs in the fight against infections. In 1937, M. E. Massengill decided to release a liquid form of the drug for children. Sulfanilamide is poorly soluble in ordinary solvents, so various substances were tested to dissolve it, of which diethylene glycol, a toxic solvent and a chemical analogue of antifreeze, turned out to be the most suitable. Preclinical and clinical studies have not been conducted. In October 1937, the FDA received a report of the death of 8 children and 1 adult patient after taking the drug. The manufacturing company has taken various measures to withdraw the drug from circulation. However, what was already sold claimed the lives of 107 people, most of whom were children.

The impetus for the development of comprehensive rules for conducting clinical trials was the thalidomide disaster that occurred between 1959 and 1961. The drug, which had not undergone sufficient preclinical and clinical studies, began to be sold in Europe as a sedative to help fall asleep and as a drug for morning sickness, recommended for use by pregnant women. From 1956 to 1962, more than 10 thousand children around the world were born with developmental defects caused by taking thalidomide.

On prisoners of the Dachau concentration camp, German doctors studied the body's reactions to high altitudes and thin air - they simulated the effect of a lack of oxygen in atmospheric conditions at an altitude of 12 km. Usually within half an hour the subject died; at the same time, in the protocol of the experiment, with German pedantry, the stages of his dying torments were recorded (such as “spasmodic convulsions”, “agonistic convulsive breathing”, “groans”, “high-pitched screams”, “grimaces, biting his own tongue”, “inability to respond to speech” and so on.). The body's reactions to hypothermia were also studied, for which naked subjects were kept in cold temperatures of up to 29 degrees for 9-14 hours or immersed in ice water for several hours. In the same concentration camp, experiments were carried out during which over 1,200 people were infected with malaria. 30 subjects died directly from the infection, from 300 to 400 from complications caused by it, and many others from an overdose of neosalvarin and pyramidon.

In Sachsenhausen and some other concentration camps, experiments were carried out with mustard gas: subjects were deliberately injured. And then the wounds became infected with mustard gas. Others were forced to inhale the gas or ingest it in liquefied form. The “experimenters” calmly recorded that when gas is injected into wounds on the hands, the hands become very swollen, and the person experiences extreme pain.

The experiments, carried out mainly on women at the Ravensbrück concentration camp, studied wound infections, as well as the possibilities of bone, muscle and nerve regeneration and bone transplantation. Incisions were made on the subjects' legs, and then bacterial cultures and pieces of wood shavings or glass were injected into the wounds. Only after a few days did they begin to treat the wounds, testing certain remedies. In other cases, gangrene occurred, after which some subjects were treated, while others - from the control groups - were left without treatment.

Other experiments on concentration camp prisoners examined infectious jaundice; methods were developed for cheap, insensitive and rapid sterilization of people; mass infection of people with typhus was carried out; the speed and nature of the action of poisons were studied; The effects of phosphorus compounds contained in incendiary bombs on the body were tested.

These and many other data, confirmed during the tribunal by documents and testimony, not only shocked the world community, but also made us think about the problem of protecting the rights, dignity and health of subjects, and the need to limit research on humans to a certain framework.

The modern world history of protecting the rights of test subjects begins with the Nuremberg Code. It was developed during the Nuremberg trials and was the first international document containing a list of ethical and legal principles for conducting research on humans. It was prepared by two American medical experts who participated in the trial - Leo Alexander and Andrew Ivy - and became an integral part of the decision made by the court.

The preamble to the Code stated: “The weight of the evidence before us forces us to conclude that certain types of medical experimentation on humans are consistent with the ethical standards of the medical profession as a whole only if they are carried out within appropriate, clearly defined boundaries.” Even though the Code was adopted in the form of a court decision, it has moral force. It includes 10 provisions.

The first provision states “the need for voluntary consent of the experimental subject” to participate in the study. It means that

- “the person involved in the experiment” must have the “legal right to give such consent” (i.e. must be recognized as legally competent)

such consent must be given freely, “without any element of force, deception, fraud, cunning or other hidden forms of coercion”;

the person giving such consent must have “sufficient knowledge to understand the nature of the subject of the experiment and make an informed decision.” To do this, the person must be informed “of the nature, duration and purpose of the experiment; the method and means by which it will be carried out; about all possible inconveniences and risks; about the consequences for one’s health or personality that may arise in the experiment.”

The essence of the remaining provisions of the Code is the requirement to minimize possible risks, as well as “all physical and mental suffering and damage”; guarantees that the study will be conducted by qualified specialists, as well as respect for the subject’s right to refuse to participate in the study at any stage of its conduct.

For quite a long time, the Nuremberg Code did not attract serious attention, and the atrocities of German doctors were considered as an isolated historical episode. But an article by Harvard Medical School professor of anesthesiology Henry Beecher forced doctors and the public to turn to this topic. In the article “Ethics and Clinical Research” (1966), the author describes 22 cases in the United States of conducting research “at risk to the life and health of the subjects,” without informing them of the dangers and without obtaining their consent.

Two examples given by Beecher are especially famous. One case involved a study conducted at a residential home for developmentally delayed children in Willowbrook, New York. To study the etiology of the disease and develop a protective vaccine, children were infected with hepatitis B. In another case, doctors injected live cancer cells into elderly and frail patients at a New York hospital.

Not long ago, documents appeared indicating inhumane experiments in the USSR. For example, in 1926, the KGB worked on the production of poisons that would not leave traces in the body, and then medications, under the influence of which a person would give “frank” and “truthful” testimony.

The effect of these drugs was tested on subjects - mainly under investigation and prisoners. It was also reported that during nuclear weapons tests, the effects of radiation on military personnel were studied.

The next stage is the “Declaration of Helsinki”, which has the subtitle “Guidelines for doctors conducting biomedical research on humans”, despite the advisory nature of the document, its provisions are reflected and developed in a number of other international regulatory documents, as well as in the national legislation of many countries, including Russia.

The “Declaration” distinguishes between biomedical research that pursues diagnostic and therapeutic purposes and is carried out in the interests of the patient - “clinical research” (“therapeutic research”) and research that primarily pursues purely scientific goals and does not have direct diagnostic or therapeutic value. for the subject, “non-clinical studies” (“non-therapeutic studies”). The text of the “Declaration” is divided into 3 parts, the first of which contains a list of the most general provisions that should be followed when conducting research on humans, the other two contain specific recommendations for conducting clinical and non-clinical research.

The main provisions of the Declaration of Helsinki of the World Medical Association:

When conducting biomedical research or solving educational and methodological problems using biological objects (human corpses or organs) and laboratory animals, legal and ethical standards must be strictly observed;

The experiment should be planned based on an in-depth study of the problem according to the literature;

The experiment must be carefully justified and aimed at obtaining results not achievable by other methods;

When experimenting on animals, care must be taken to avoid unnecessary physical suffering or injury;

The experiment must be carried out by qualified specialists, and the training must be carried out under the guidance of qualified teachers;

At all stages of research or educational work, the maximum level of attention and skill must be ensured by both the organizers and all participants in the process;

Precautionary measures must be observed to ensure the safety of personnel and eliminate possible negative impacts on the environment.

In November 1996, the Parliamentary Assembly of the Council of Europe adopted the Convention on Human Rights and Biomedicine, which, unlike the 2 above-mentioned documents, also applies to the use of the results of these studies in medical practice, and it itself is already an element of international law and contains the obligation of the signatories its parties “to take all necessary steps to improve their national legislation so that it reflects the provisions of this Convention” (Article 1).

The basic principle is “the interests and good of the individual must prevail over the interests of society and science” (Article 2).

All medical interventions can only be carried out with the consent of the persons to whom they are carried out; such consent must be voluntary and informed (Article 5). At the same time, the rights and interests of persons who are unable or unable to give consent on their own must be protected (Articles 6-9).

It is necessary to respect the principle of privacy, as well as respect the person’s right to know (or not know) information about the state of his health;

Any discrimination based on information about the genetic characteristics of a person is prohibited (Article 11). It is prohibited to interfere with the human genome for the purpose of changing the genome of his descendants (Article 12). It is prohibited to choose the sex of the unborn child, except in cases where it is a question of avoiding a serious disease linked to sex (Article 14).

Scientific research must be carried out in compliance with the provisions of the “Convention” and other legal instruments aimed at protecting the rights, dignity and interests of the individual (Article 15.). The creation of human embryos for research purposes is prohibited (Article 18).

The collection of organs or tissues from a living donor for the purpose of their further transplantation can only be carried out with his consent and exclusively for therapeutic purposes (Article 19). The human body itself, as well as its individual parts, should not be considered and serve as a source of financial gain (Article 21).

In 1997, in connection with reports of successful experiments in cloning mammals and discussions of the prospects for applying this technology to humans, the Council of Europe adopted an “Additional Protocol” to the “Convention”. It prohibits “any intervention intended to create a human being that is genetically identical to another human being, living or dead.”

biological moral experiment clinical

Concept and types of biomedical research

Research on humans is divided into two types: biomedical research (non-clinical) and clinical research. Biomedical research studies the reaction and changes in the state of the body of healthy people when exposed to certain external factors. Such studies complement and improve scientific data, but are not directly related to the treatment of diseases. Clinical studies are carried out in the process of treating diseases. These studies follow clear rules that exclude factors that distort the results. To determine the effectiveness of medical intervention, an experimental and control group is needed, the number of subjects in each group must be at least 100, in order to identify clear analogies, the groups must be approximately the same in age, gender, and severity of the disease. Any research is ethical when it is meaningful and well organized.

There is a specific group of people who are considered “vulnerable”. It is customary to call “vulnerable”, first of all, children, subjects with mental disorders, pregnant women, military personnel, medical students, and prisoners. These groups are “vulnerable” because, for various reasons, they are not completely free from the coercion of the experimenter, their superiors, or their position. Possible risk of harm and abuse. In Russia, testing on pregnant women, fetuses, newborns and prisoners is prohibited, although it could give them a chance of a cure. But in extreme cases, if the study is necessary and will help solve the problem of a given group and a given patient, then its conduct may be specifically reviewed by an ethics committee.

Principles and rules for conducting medical research

The normal development of medicine is impossible without constantly conducting clinical trials and biomedical experiments on humans. Objective knowledge is a fundamental social value and can therefore justify possible risks to the bodily and social well-being of people acting as “subjects” of research activities.

At the same time, no matter how high the value of objective knowledge, in all cases it must be commensurate with no less, and often more significant social values, which can be formulated in the form of principles:

respect for a person as an individual;

charity and mercy;

justice;

solidarity.

The basic ethical principles for conducting medical research are as follows:

1. Respect for a person as an individual comes from recognition and respect for the self-sufficient importance of his free will, the right and opportunity to play a decisive role in making decisions affecting his bodily and (or) social well-being. A person should be considered as the “master” of his body, without whose conscious and voluntary permission, in principle, no manipulations should be carried out: research, preventive, diagnostic and therapeutic. He also has certain rights to access, control and dispose of clinical, medical-biological and other information obtained by physicians as part of their research.

A person is respected as an individual if he is actually recognized as the responsible “author” of his unique and unique life story (biography).

The principle of charity and mercy is at the core of the calling of doctors and other health professionals. He directs physicians, out of a sense of compassion, to be guided primarily by the good of this particular patient, relegating other motives of their activity to the background: cognitive, pedagogical, commercial, etc.

Justice presupposes fundamental equality of opportunity for people in terms of: a) access to medical care and distributed medical services; b) the likelihood of sharing the burden of risk to health and life, suffering and responsibility.

4. Medicine is the oldest and most important form of solidarity as a principle that ensures the survival of the individual and humanity as a whole. Illness and injury affect our common perspectives and interests. It is therefore in our common interests to promote, as far as possible, the progress of medical science and practice. A person's willingness, out of a sense of solidarity, to voluntarily participate as a “subject” of clinical trials and biomedical experiments should be respected.

The principles formulated above relate to each other according to the principle of complementarity and are not in a relationship of hierarchical dependence.

Rules for testing and experiments:

1. Free, informed (informed) consent to participate in a medical-biological experiment or clinical trial, recorded in the form of a written agreement between the doctor who is in charge of the trial or experiment, and the patient (or subject), is a strictly mandatory condition for their conduct.

Responsibility for information and its adequacy lies with the manager and cannot be forwarded to third parties.

The patient (subject) has the right to refuse to participate in the study at any stage, while retaining all rights to quality medical care provided for by law and the service agreement previously concluded between him and the institution. If the subject is incapacitated, voluntary informed consent must be obtained from a guardian in accordance with the law.

Tests and experiments on humans are justified only if the planned significant increase in knowledge cannot be obtained in other ways: through a thorough and sufficient study of scientific medical literature, conducting experiments on animals or artificial model systems, computer modeling, etc. d.

Research on humans is permissible only in cases where the planned scientific result is reliably justified as probable from the point of view of the achieved level of development of medical science. It is unacceptable to conduct random experiments at random.

4. Only such research on humans can be morally justified if, in its ideology, methodology and technique, it corresponds to the standards of modern medical science.

Research on humans that is based on outdated theories, using outdated methodology and techniques that a priori reduce the scientific significance of the knowledge obtained should be considered immoral.

The degree of risk to the life, physical and social well-being of the subject should not exceed the scientific significance of the planned results. The interests of the person acting as the “object” of research should be recognized above the interests of humanity in obtaining objective knowledge.

Tests and experiments should be designed to minimize the risk of adverse effects. The “materials and methods” of the study must strictly include means sufficient for prompt relief of possible negative consequences and complications. This also requires the mandatory participation of relevant specialists in the study.

Clinical trials and medical and biological experiments on humans can only be carried out by a team of specialists led by a doctor, corresponding to the nature of the qualification research.

Applications for clinical trials and biomedical experiments, including personally signed statements that all researchers are informed and undertake to comply with these rules, as well as draft “Informed Consent Forms” for participation in research for all categories of subjects must undergo mandatory approval independent from the researchers “Ethics Committee”.

Biomedical research on humans can be carried out by doctors in the following cases:

if they serve to improve the health of patients participating in the experiment;

if they make a significant contribution to medical science and practice;

if the results of previous studies and scientific literature do not indicate a risk of complications.

The results of research and experiments must be published in the professional literature, otherwise they will not be independently verified and will be meaningless. When describing the progress and results of tests, the rule of confidentiality must be observed so as not to cause moral, material or other damage to the person participating in the experiment. The results of the experiment must not be distorted, exaggerated, premature or unverified. After publication, copyright comes into force; use of information without indicating the authors will be considered illegal.

Literature

1. Lopatin P.V.: Bioethics. - M.: GEOTAR-Media, 2011

2. Khrustalev Yu.M.: Introduction to biomedical ethics. - M.: Academy, 2010

3. Lopatin, P.V.: Bioethics. - M.: GEOTAR-Media, 2008

4. State Educational Institution of Higher Professional Education "Kazan State Medical University" of the Federal Agency for Health and Social Development of the Russian Federation, Student Scientific Society of KSMU: Collection of abstracts. - Kazan: KSMU, 2007

5. Lopatin P.V.: Bioethics. - M.: GEOTAR-Media, 2006

6. Brek I.: The sacred gift of life. - M.: Pilgrim, 2004

7. T.V. Mishatkina, Z.V. Brazhnikova, N.I. Mushinsky and others; Under general ed.: T.V. Mishatkina, Ya.S. Yaskevich; Rec.: department philosophy of Gomel State. University, S.P. Vinokurova; Yu.A. Gusev: Ethics. - Minsk: New knowledge, 2002

8. Ministry of Health of the Russian Federation, State Educational Institution VUNMC for continuing medical and pharmaceutical education; I.V. Siluyanova, V.A. Antipenkov, T.F. Korableva, M.S. Pershin; Rec.: Yu.M. Khrustalev, N.N. Sedova, I.A. Serova: Questions of test control in the discipline "Biomedical Ethics". - M.: VUNMTs, 2000

9. Mitcham K.: What is the philosophy of technology?. - M.: Aspect Press, 1995

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The need for clinical trials

Each new medical product (drug, device) must undergo clinical trials. Particular attention was paid to clinical trials at the end of the 20th century, in connection with the development of the concept of evidence-based medicine.

Authorized control bodies

In most countries of the world, ministries of health have special departments responsible for checking the results of clinical trials conducted on new drugs and issuing permits for the entry of a medical product (drug, device) into the pharmacy chain.

IN THE USA

For example, in the United States, such a department is Food and Drug Administration (

In Russia

In Russia, the functions of supervision of clinical trials conducted in Russia are carried out by the Federal Service for Surveillance in Healthcare and Social Development (Roszdravnadzor of the Russian Federation).

Since the beginning of the era of clinical trials (CT) in the early 1990s, the number of studies conducted in Russia has been steadily growing from year to year. This is especially noticeable in the example of international multicenter clinical trials (IMCTs), the number of which has increased almost fivefold over the past ten years - from 75 in 1997 to 369 in 2007. The share of IMCTs in the total volume of clinical trials in Russia is also growing - if ten years ago they were only 36%, then in 2007 their share increased to 66% of the total number of clinical trials. This is an important positive indicator of the “health” of the market, reflecting the high degree of confidence of foreign sponsors in Russia as a developing CI market.

Data received from Russian research centers are unconditionally accepted by foreign regulatory authorities when registering new drugs. This applies to both the American Food and Drug Administration (FDA) and the European Agency for the Evaluation of Medicinal Products (EMEA). For example, six of the 19 new molecular substances approved by the FDA in 2007 underwent clinical trials with the participation of Russian research centers.

Another important factor in the increase in the number of IMCTs in Russia is the increase in its commercial attractiveness for foreign sponsors. The growth rate of the retail commercial market in Russia is three to four times higher than the growth rate of pharmaceutical markets in Europe or the USA. In 2007, growth in Russia was 16.5%, and the absolute sales volume of all medicinal products reached 7.8 billion US dollars. This trend will continue in the future thanks to the effective demand of the population, which, according to experts from the Ministry of Economy and Trade Development, will grow steadily over the next eight years. This suggests that if, through the joint efforts of market participants, Russia can move closer to the pan-European deadlines for obtaining approvals for clinical trials, then with its good patient recruitment and further stabilization of the political and regulatory climate, it will soon become one of the world's leading markets for clinical trials.

In 2007, Roszdravnadzor of the Russian Federation issued 563 permits for all types of clinical trials, which is 11% more than in 2006. The growth in indicators should mainly be attributed to an increase in the number of international multicenter clinical trials (IMCTs) (by 14%) and locally conducted clinical trials (an increase of 18% per year). According to forecasts from Synergy Research Group, which conducts quarterly monitoring of the clinical research market in Russia (Orange Book), in 2008 the number of new studies will fluctuate at 650, and by 2012 it will reach a thousand new CTs per year.

Control practices in other countries

Similar institutions exist in other countries.

International requirements

The basis for conducting clinical studies (tests) is the document of the international organization “International Conference on Harmonization” (ICH). This document is called "Guideline for Good Clinical Practice" ("Description of the GCP standard"; Good Clinical Practice is translated as "Good Clinical Practice").

Typically, in addition to doctors, other clinical research specialists work in the field of clinical research.

Clinical trials must be conducted in accordance with the fundamental ethical principles of the Declaration of Helsinki, GCP standard and applicable regulatory requirements. Before the start of a clinical trial, an assessment must be made of the relationship between the foreseeable risk and the expected benefit for the subject and society. The principle of priority of the rights, safety and health of the subject over the interests of science and society is put at the forefront. The subject can be included in the study only on the basis voluntary informed consent(IS), obtained after a detailed review of the research materials. This consent is certified by the signature of the patient (subject, volunteer).

The clinical trial must be scientifically justified and described in detail and clearly in the study protocol. The assessment of the balance of risks and benefits, as well as the review and approval of the study protocol and other documentation related to the conduct of clinical trials, are the responsibilities of the Institutional Review Board/Independent Ethics Committee (IRB/IEC). Once approval has been received from the IRB/IEC, the clinical trial can begin.

Types of clinical trials

Pilot the study is intended to obtain preliminary data important for planning further stages of the study (determining the possibility of conducting a study with a larger number of subjects, sample size in a future study, required study power, etc.).

Randomized a clinical trial in which patients are randomly assigned to treatment groups (randomization procedure) and given equal opportunity to receive the study drug or a control drug (comparator or placebo). In a non-randomized study, there is no randomization procedure.

Controlled(sometimes used as a synonym "comparative") a clinical trial in which an investigational drug, the effectiveness and safety of which has not yet been fully established, is compared with a drug whose effectiveness and safety are well known (comparator). This may be a placebo (placebo-controlled trial), standard therapy, or no treatment at all. In an uncontrolled (non-comparative) study, a control/comparison group (a group of subjects taking a comparison drug) is not used. In a broader sense, controlled research refers to any study in which potential sources of bias are controlled (minimized or eliminated as much as possible) (i.e., it is carried out in strict accordance with the protocol, monitored, etc.).

When conducting parallel In studies, subjects in different groups receive either only the study drug or only a comparator/placebo drug. IN cross In studies, each patient receives both drugs being compared, usually in random order.

The study may be open when all study participants know which drug the patient is receiving, and blind(masked) when one (single-blind study) or more parties participating in the study (double-blind, triple-blind or completely blind study) are kept in the dark about the allocation of patients to treatment groups.

Prospective A study is conducted by dividing participants into groups that will or will not receive the study drug before the outcomes occur. In contrast, a retrospective (historical) study examines the outcomes of previously conducted clinical trials, that is, the outcomes occur before the study began.

Depending on the number of research centers in which the study is conducted in accordance with a single protocol, studies may be single-center And multicenter. If a study is conducted in several countries, it is called international.

IN parallel The study compares two or more groups of subjects, one or more of which receive the study drug and one group is the control. Some parallel studies compare different treatments without including a control group. (This design is called an independent groups design.)

Cohort A study is an observational study in which a selected group of people (cohort) is followed over time. Outcomes of subjects in different subgroups of a given cohort, those who were or were not exposed (or exposed to varying degrees) to the study drug, are compared. IN prospective cohort In the study, cohorts are formed in the present and observed in the future. In a retrospective (or historical) cohort study, a cohort is selected from historical records and their outcomes are followed from then to the present. Cohort trials are not used to test drugs, but rather to determine the risk of exposures that cannot be controlled or ethically controlled (smoking, excess weight, etc.).

In the study case-control(synonym: case study) compare people with a particular disease or outcome (“case”) with people from the same population who do not have the disease or who did not experience the outcome (“control”), with the goal of identifying the relationship between the outcome and prior exposure to certain risks. factors. A case series study follows several individuals, usually receiving the same treatment, without the use of a control group. A case report (synonyms: case report, case report, single case report) examines treatment and outcome in one person.

Double-blind, randomized, placebo-controlled trial- a method of testing a medicinal product (or treatment technique), in which the influence on the patient of both unknown factors and psychological factors is taken into account and excluded from the results. The purpose of the trial is to test the effect of only the drug (or technique) and nothing else.

When testing a drug or technique, experimenters usually do not have enough time or resources to reliably determine whether the treatment being tested produces a sufficient effect, so statistical methods are used in a limited clinical trial. Many diseases are very difficult to cure and doctors have to fight for every step towards recovery. Therefore, the test monitors multiple symptoms of the disease and how they change with exposure.

A cruel joke can be played by the fact that many symptoms are not strictly related to the disease. They are not unambiguous for different people and are subject to influence from the psyche of even an individual: under the influence of the doctor’s kind words and/or the doctor’s confidence, the patient’s degree of optimism, symptoms and well-being can improve, and objective indicators of immunity often increase. It is also possible that there will be no real improvement, but the subjective quality of life will increase. Symptoms may be influenced by unaccounted factors, such as the patient’s race, age, gender, etc., which will also indicate something other than the effect of the drug under study.

To cut off these and other effects that blur the influence of the treatment technique, the following techniques are used:

research is being done placebo-controlled. That is, patients are divided into two groups, one - the main one - receives the study drug, and the other, the control group, is given a placebo - a dummy.

research is being done blind(English) single blind). That is, patients do not realize that some of them are not receiving a new drug being studied, but a placebo. As a result, patients in the placebo group also think they are receiving treatment when in fact they are receiving a dummy. Therefore, the positive dynamics from the placebo effect occurs in both groups and disappears during comparison.

IN double blind(double blind) in the study, not only the patients, but also the doctors and nurses who give the medicine to the patients, and even the clinic management themselves do not know what they are giving them - whether the drug being studied is really a placebo. This excludes the positive impact of confidence on the part of doctors, clinic management and medical staff.

Clinical trials of the drug are a necessary stage 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 scientific assessments and evidence of the effectiveness and safety of medicines. However, these studies cannot provide reliable information about how the drugs being studied will act in humans, since the organism of laboratory animals differs from humans both in pharmacokinetic characteristics and in the response of organs and systems to drugs. Therefore, clinical trials of drugs in humans are necessary.

So what is clinical trial (test) of a medicinal product? This is a systemic study of a medicinal product through its use in humans (patient or healthy volunteer) with the aim of assessing its safety and/or effectiveness, as well as identifying and/or confirming its clinical, pharmacological, pharmacodynamic properties, assessing absorption, distribution, metabolism, excretion and /or interactions with other drugs. The decision to initiate a clinical trial is made by Sponsor/Customer, who is responsible for organizing, supervising and/or funding the study. Responsibility for the practical implementation of the study rests with Researcher(person or group of persons). As a rule, the sponsor is a pharmaceutical company that develops drugs, but a 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, GCP Regulations ( Good Clinical Practice, Good Clinical Practice) and applicable regulatory requirements. Before the start of a clinical trial, an assessment must be made of the relationship between the foreseeable risk and the expected benefit for the subject and society. The principle of priority of the rights, safety and health of the subject over the interests of science and society is put at the forefront. The subject can be included in the study only on the basis voluntary informed consent(IS), obtained after a detailed review of the research materials.

The clinical trial must be scientifically justified, detailed and clearly described in research protocol. Assessing the balance of risks and benefits, as well as reviewing and approving the study protocol and other documentation associated with the conduct of clinical trials are the responsibility of Expert Council of the Organization / Independent Ethics Committee(ESO/NEC). Once approval has been received from the IRB/IEC, the clinical trial can begin.

Types of clinical trials

Pilot study is intended to obtain preliminary data important for planning further stages of the study (determining the possibility of conducting a study with a larger number of subjects, the sample size in a future study, the required power of the study, etc.).

Randomized clinical trial, in which patients are randomly assigned to treatment groups (randomization procedure) and have equal opportunity to receive the study drug or the control drug (comparator or placebo). In a non-randomized study, there is no randomization procedure.

Controlled(sometimes used as a synonym "comparative") a clinical trial in which an investigational drug, the effectiveness and safety of which has not yet been fully established, is compared with a drug whose effectiveness and safety are well known (comparator). This could be a placebo, standard therapy, or no treatment at all. IN uncontrolled In a (non-comparative) study, a control/comparison group (a group of subjects taking a comparison drug) is not used. In a broader sense, a controlled study refers to any study in which potential sources of systematic error are controlled (minimized or eliminated if possible) (i.e., it is carried out in strict accordance with the protocol, monitored, etc.).

When conducting parallel research subjects in different groups receive either only the study drug or only the comparator/placebo drug. IN cross-sectional studies each patient receives both drugs being compared, usually in random order.

The study may be open when all study participants know which drug the patient is receiving, and blind (disguised) when one (single-blind study) or more parties participating in the study (double-blind, triple-blind or completely blind study) are kept in the dark about the allocation of patients to treatment groups.

Prospective study is conducted by dividing participants into groups that will or will not receive the study drug before the outcomes occur. In contrast to him, in retrospective(historical) research examines the outcomes of previously conducted clinical trials, i.e. outcomes occur before the study begins.

IN parallel study two or more groups of subjects are compared, one or more of which receive the study drug, and one group is the control. Some parallel studies compare different treatments without including a control group. (This design is called an independent groups design.)

Cohort study is an observational study in which a selected group of people (cohort) is observed over a period of time. Outcomes of subjects in different subgroups of a given cohort, those who were or were not exposed (or exposed to varying degrees) to the study drug, are compared. IN prospective cohort study cohorts are formed in the present and observed in the future. IN retrospective(or historical) cohort study the cohort is selected from archival records and their outcomes are tracked from that time to the present.

IN case-control study(synonym: case study) compare people with a particular disease or outcome (“case”) with people from the same population who do not have the disease or who did not experience the outcome (“control”), with the goal of identifying the relationship between the outcome and prior exposure to certain risks. factors. In the study case series several individuals are observed, usually receiving the same treatment, without the use of a control group. IN case description(synonyms: case report, medical history, description of a single case) is a study of treatment and outcome in one person.

Currently, preference is given to the design of clinical drug trials that provides the most reliable data, for example, by conducting prospective controlled comparative randomized and, preferably, double-blind studies.

Recently, the role of clinical trials of drugs has increased due to the introduction of the principles of evidence-based medicine into practical healthcare. And chief among them is making specific clinical decisions for patient treatment based on rigorous scientific evidence that can be obtained through well-designed, controlled clinical trials.

Concept and types of biomedical research

Human studies are divided into two types:

1)medical and biological research (non-clinical)

2) clinical studies.

Biomedical research studies the reaction and changes in the state of the body of healthy people when exposed to certain external factors. Such studies complement and improve scientific data, but are not directly related to the treatment of diseases.

Clinical studies are carried out in the process of treating diseases. These studies follow clear rules that exclude factors that distort the results. To determine the effectiveness of medical intervention, an experimental and control group is needed, the number of subjects in each group must be at least 100, in order to identify clear analogies, the groups must be approximately the same in age, gender, and severity of the disease. Any research is ethical when it is meaningful and well organized.

The normal development of medicine is impossible without constantly conducting clinical trials and biomedical experiments on humans.

respect for a person as an individual;

charity and mercy;

justice;

solidarity.

The basic ethical principles for conducting medical research are as follows:

2 Justice presupposes fundamental equality of opportunity for people in terms of: a) access to medical care and distributed medical services; b) the likelihood of sharing the burden of risk to health and life, suffering and responsibility.

3. . Only such research on humans can be morally justified if, in its ideology, methodology and methodology, it corresponds to the standards of modern medical science.

4 Clinical trials and medical and biological experiments on humans can only be carried out by a team of specialists led by a doctor, corresponding to the nature of the qualification research.

Regulations for the regulation of biomedical research.

1) Tests and experiments begin subject to full and accessible information to the patient and receipt of his explicit consent, expressed in writing.

2) The researcher must guarantee the patient’s right to refuse to continue the study at any stage and for any reason. The subject can feel not only physical pain, but also emotional discomfort, fear, and prejudice. If the test is harmful or life-threatening to the patient, it must be stopped immediately.

3) If the patient is unable to give informed consent to participate in the study, it may be obtained in writing from a parent, guardian or other legally responsible person.

Biomedical research on humans can be carried out by doctors in the following cases:

1) if they serve to improve the health of patients participating in the experiment;

2) if they make a significant contribution to medical science and practice;

3) if the results of previous studies and scientific literature do not indicate a risk of complications.

Animal experimentation is necessary:

1) in cases where animal populations are studied;

2) in those cases in which, according to the experimental conditions, it is necessary to study the reaction of the entire organism, the mutual influence of organs and systems, the sequence of failure (or healing) of various organs and systems;

3) when conducting final experiments on the processing of new surgical techniques;

4) when it is necessary to study individual results of exposure;

5) when the organs and systems of the animal cannot be isolated;

6) - for research on isolated organs;

7) - when animals are used to obtain biological products (vaccines, serums, etc.).

Given this circumstance, animal experiments must comply with strict ethical standards:

1) the goals are approved by society and the ethical committee, based on the principle of humanism;

2) effective pain relief is used;

3) the necessary care is provided;

4) animals are not used in repeated experiments that turn their lives into continuous suffering;

5) death is painless;

6) experiments are carried out by trained persons to avoid unnecessary suffering;

International ethical and legal regulation of biomedical research:

- “Nuremberg Code” on biomedical research on humans and the “Declaration of Helsinki” of the WMA as fundamental sources of modern moral standards for conducting experiments and clinical trials on humans.

- Council of Europe Convention on Human Rights and Biomedicine.

1. "Nuremberg Code"

The modern history of discussion of these problems begins, perhaps, with the end of the Second World War.

The peculiarity was the particularly cruel, inhumane nature of the experiments: the death of the subjects was actually planned in them. The experiments carried out by the Nazis are described below:

1) as a study of the body’s reaction to high altitudes and rarefied air: the effects of a lack of oxygen in atmospheric conditions at an altitude of 12 km were simulated on subjects - prisoners of the Dachau concentration camp. Usually within half an hour the subject died; at the same time, in the protocol of the experiment, with German pedantry, the stages of his dying torments were recorded (such as “spasmodic convulsions”, “agonistic convulsive breathing”, “groans”, “high-pitched screams”, “grimaces, biting his own tongue”, “inability to respond to speech” and so on.)

2) The body’s reactions to hypothermia were also studied, for which naked subjects were kept in cold temperatures up to 29 degrees for 9-14 hours or immersed in ice water for several hours.

3) Experiments conducted mainly on women at the Ravensbrück concentration camp studied wound infections, as well as the possibilities of bone, muscle and nerve regeneration and bone transplantation. Incisions were made on the subjects' legs, and then bacterial cultures and pieces of wood shavings or glass were injected into the wounds. Only after a few days did they begin to treat the wounds, testing certain remedies. In other cases, gangrene occurred, after which some subjects were treated, while others - from the control groups - were left without treatment.

4) In other experiments, infectious jaundice was studied on concentration camp prisoners; methods were developed for cheap, insensitive and rapid sterilization of people; mass infection of people with typhus was carried out; the speed and nature of the action of poisons were studied; The effects of phosphorus compounds contained in incendiary bombs on the body were tested.

During the Nuremberg trials, a document was developed that was called the “Nuremberg Code” and was essentially the first international document containing a list of ethical and legal principles for conducting research on humans. It was prepared by two American medical experts who participated in the trial - Leo Alexander and Andrew Ivy - and became an integral part of the decision made by the court.

Ten principles of the code (may be repeated)

1. An absolutely necessary condition for conducting an experiment on a person is the voluntary consent of the latter.

2. The experiment must bring positive results to society that are unattainable by other methods or methods of research; it should not be random, optional in nature.

3. The experiment must be based on data obtained in laboratory studies on animals, knowledge of the history of the development of the disease or other problems being studied. Its implementation must be organized in such a way that the expected results justify the very fact of its implementation.

4. When conducting an experiment, all unnecessary physical and mental suffering and injury must be avoided.

5. No experiment should be carried out if there is reason to assume the possibility of death or disabling injury to the subject; An exception may be cases where medical researchers act as subjects during their experiments.

6. The degree of risk associated with conducting an experiment should never exceed the humanitarian importance of the problem that the experiment is aimed at solving.

7. The experiment must be preceded by appropriate preparation, and its conduct must be provided with equipment necessary to protect the subject from the slightest possibility of injury, disability or death.

8. The experiment should only be carried out by scientifically qualified persons. At all stages of the experiment, maximum attention and professionalism is required from those who conduct it or are involved in it.

9. During the experiment, the subject must have the opportunity to stop it if, in his opinion, his physical or mental condition makes it impossible to continue the experiment.

10. During an experiment, the investigator responsible for its conduct must be prepared to terminate it at any stage if professional considerations, good faith and the care in judgment required of him indicate that continuation of the experiment would lead to injury, disability or death. test subject.

Declaration of Helsinki- developed by the World Medical Association, is a set of ethical principles for the medical community regarding human experimentation. The first version was adopted in June 1964 in Helsinki, Finland, and has since undergone nine revisions, the most recent of which was the Declaration, which expands on the principles first formulated in the Nuremberg Code and applies these ideas directly to clinical research work.

(A couple of principles and rules of this declaration)

1) A physician may combine medical research with the provision of medical care only if the research is justified by its potential preventive, diagnostic or therapeutic value

2) A physician may combine medical research with the provision of medical care only if the research is justified by its potential preventive, diagnostic or therapeutic value, and if the physician has reasonable grounds to believe that participation in the research study will not harm the health of the patient subjects. research.

3) At the end of the study, patients who participated in the study have the right to information about the results of the study, as well as the right to receive any benefits obtained as a result of the study, such as access to interventions identified as beneficial in the study or access to other appropriate health care , or other benefits.

- Council of Europe Convention on Human Rights and Biomedicine. It includes

1. It is necessary to respect the principle of privacy, as well as respect the right of a person to know (or not know) information about the state of his health (Article 10).
2. Any form of discrimination based on information about the genetic characteristics of a person is prohibited

3. "The interests and welfare of the individual must prevail over the interests of society and science"

4. Removal of organs or tissues from a living donor for the purpose of their further transplantation can only be carried out with his consent and exclusively for therapeutic purposes (Article 19). By itself

5. The right of scientists to conduct scientific research must be respected, but the latter must be carried out in compliance with the provisions of this “Convention” and other legal instruments aimed at protecting the rights, dignity and interests of the individual (Article 15). The creation of human embryos for research purposes is prohibited

AND IN THE LECTURE YOU NEED TO TAKE INFORMATION ABOUT WHEN YOU CAN CONDUCT RESEARCH WITHOUT THE CONSENT OF PATIENTS!!! SHE MADE AN EMPHASIS ON THIS

Planning and conducting clinical trials of drugs

Clinical trials of the drug are a necessary step in the development of any new drug. 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 scientific assessments and evidence of the effectiveness and safety of medicines. However, these studies cannot provide reliable information about how the drugs being studied will work in humans. Therefore, clinical trials of drugs in humans are necessary.

Clinical study (test) of a medicinal product- This is a systemic study of a drug through its use in humans (patient or healthy volunteer) in order to assess its safety and/or effectiveness, as well as identify and/or confirm its clinical, pharmacological, pharmacodynamic properties, assess absorption, distribution, metabolism, excretion and/or interactions with other drugs. The decision to initiate a clinical trial is made by

Sponsor/Customer, who is responsible for organizing, supervising and/or funding the study. Responsibility for the practical implementation of the study rests with Researcher(person or group of persons). As a rule, the sponsor is a pharmaceutical company that develops drugs, but a 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