With the world by thread: how the components of a clinical trial were connected. Ethical Issues in Conducting Clinical Trials and Experiments on Humans Clinical Research Without Human Subjects

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. On initial stages development medicines 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 body of laboratory animals differs from humans both in pharmacokinetic characteristics and in the response of organs and systems to drugs. Therefore, it is necessary to carry out clinical trials medicines in humans.

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 pharmaceutical companies– developers of medicines, however, a researcher can also act as a sponsor if the study was started 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 various 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.

Depending on quantity research centers, in which research is carried out in accordance with a single protocol, studies can be single-center And multicenter. If a study is conducted in several countries, it is called international.

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 this cohort, those who were or were not exposed (or were exposed in to varying degrees) treatment with 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.

IN Lately 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.

Very negative? After all, some remedies really help. The disadvantage of folk remedies is that the effectiveness of most of them is not tested by strict scientific methods, so there is always a high risk of error. But there is also an effect “ placebo" - self-hypnosis, when the patient convinces himself that the medicine really helps, although it may be ordinary tap water.

Last time I told you what clinical trials of drugs are like, and today I will focus on the technique of conducting them and evaluating the results.

What is GCP protocol

Regarding the production of drugs, there is an international GMP standard(good manufacturing practice - good manufacturing practice), and for clinical trials of drugs was created GCP standard(good clinical practice - good clinical practice).

Each patient participating in the trial must give written consent to treatment with the possible use of a placebo. Does he get paid? Usually not. The patient simply receives free treatment. The research protocol for a new drug must be approved Ethical Committee everyone medical institution, in which the tests are carried out. Why is this necessary? There's a fine line here. A doctor has no right to use a placebo in seriously ill patients if this could end tragically (for example, in the case of appendicitis the doctor is obliged to prescribe an operation for the patient, although there were no comparative clinical studies on the benefits of such operations, but only the observations of surgeons that without surgery, patients died). If serious complications develop, placebo should be discontinued immediately. If the patient stops taking the prescribed drug at any time, he will drop out of the study.

A report is filled out for each patient in the form of a separate card. CRF(case report form), including the original and 2 copies, one of which remains in the healthcare institution and is stored for 15 years.

Each investigator must provide detailed information about himself and must immediately inform the client company of any identified serious side effects. Some studies have been stopped early, when researchers have received convincing evidence of unfavorable treatment results (for example, a significant increase in mortality in the experimental group). But it also happens that clinical trials are stopped early if a huge benefit is identified for a new drug or treatment.

Endpoints

To evaluate the results of a study, you need to select certain parameters that will be evaluated. Parameters are sorted in order of decreasing importance (primary, secondary and tertiary endpoints).

Primary (“solid”) endpoints are parameters related to the life of patients and development life-threatening complications. The body as a whole is assessed. Examples:

total mortality,
incidence of fatal myocardial infarction, stroke, ventricular fibrillation, etc.

Secondary and tertiary points are also called “ soft" And " surrogate».

Secondary endpoints reflect the state of one or two body systems:

improved quality of life due to relief of disease symptoms (for example, reduced frequency of angina attacks),
incidence of non-fatal (non-fatal) myocardial infarction,
reduction in the incidence of non-lethal diseases (for example, paroxysm of atrial fibrillation).

Tertiary endpoints reflect changes in individual parameters, such as cholesterol levels or blood pressure.

When evaluating a new drug, the first consideration should always be: "solid" (primary) endpoints. Evaluating only “soft” points can lead to serious errors. This is probably why the points are called surrogate? Examples:

cardiac glycosides in chronic heart failure, they increase the strength of myocardial contractions (tertiary point), reduce the frequency of hospitalizations and improve quality of life (secondary points), but do not lead to a decrease in overall mortality (primary point) due to the increased incidence of fatal arrhythmias (also a primary point);
for AIDS Some drugs that increase T-helper cells (tertiary endpoint) did not reduce mortality (primary endpoint). For information: T-helpers are a type of lymphocyte that is affected by HIV.

Mega Research

The more quality research is conducted, the more reliable the results.

Mega Research(from mega- huge) - these are studies of new drugs on more than 10 thousand patients. In small groups of patients, the results are not so reliable, because in small groups:

difficult to distinguish positive result from treatment for spontaneous remissions of the disease,
it is difficult to achieve homogeneity of groups,
it is difficult to identify small positive changes in treatment and further prognosis,
difficult to identify rare side effects.

Sometimes statistically reliable data from a mega-study on the benefits of a new drug are due to the presence among a large number of patients of a small group of patients who are highly sensitive to treatment. For others, the new drug does not bring much benefit. Such patients who are highly sensitive to treatment need to be identified - because The new drug will bring maximum benefit only to them.

Scheme of a heterogeneous research model

Meta-analysis

Meta-analysis(Greek meta- through) - combining the results of several controlled studies on one topic. As the number of trials analyzed increases, new positive and negative treatment effects may be discovered that were not apparent in individual studies. Meta-analyses (meta-reviews) are by far the most important and valuable because researchers analyze the quality of many clinical studies on a given topic, some various reasons they are rejected, and conclusions are drawn from the remaining ones.

As you should know by now, when reading the results of any study, it is important to evaluate the primary endpoints first. For example, two meta-analyses found a positive antiarrhythmic effect lidocaine in myocardial infarction, and one meta-analysis was negative. What to believe? Recommend lidocaine to everyone in case of myocardial infarction? But no, since the first two meta-analyses were devoted to the effect of lidocaine on arrhythmias (i.e., assessing secondary endpoints), and the third - the effect of lidocaine on survival in myocardial infarction (primary endpoint). Thus, lidocaine successfully suppressed arrhythmias, but at the same time increased the mortality of patients.

Disadvantages of Meta-Analyses

Meta-analyses are not a substitute for mega-studies and, in some cases, may even contradict them. Meta-analyses may be unconvincing in the following cases:

if the meta-analysis gives a generalized conclusion, although the studies involved heterogeneous groups of patients. Or did treatment begin in different terms and different doses of drugs;
if the effectiveness of treatment is compared in some groups with placebo, and in others - with a known effective drug comparisons, but the conclusion is drawn as a general one. Or the nature of concomitant therapy is not taken into account;
in cases of poor randomization (separation into groups was not carried out randomly enough).

The results of meta-analyses help the doctor choose treatment, but they cannot be universal (for all cases) and cannot replace the clinical experience of the doctor.

Levels of Evidence

To distinguish how much you can trust recommendations, they were invented gradations(A, B, C) and levels of evidence(1, 2, 3, 4, 5). I was going to give this classification here, but upon closer examination I found out that all the classifications I had differed in small details, since they were adopted by different organizations. For this reason, I’ll just give one example:

This is an example of the classification of levels of evidence and gradations of recommendations

In order decreasing reliability The different types of studies are arranged in the following order (source: Swedish Council for Health Evaluation Methodology):

randomized controlled trial (i.e. having an experimental and control group with randomization),
non-randomized controlled study with simultaneous control,
non-randomized controlled trial with historical control,
case-control study,
cross-sectional controlled study, cross-sectional study,
observational results (open non-randomized study without group),
description of individual cases.

How to analyze research results

All results obtained in a clinical study are processed using methods mathematical statistics . The formulas and principles of calculations are quite complex, practitioner there is no need to know them for sure, but in a medical university at the Faculty of Medicine they are introduced to them in two physics classes in the 1st year and used in social hygiene(health care organizations) in the 6th year. Organizers of clinical trials carry out all calculations independently using statistical software packages.

1) Statistical reliability. In medicine, any quantity is considered statistically reliable, if it is determined with a probability of 95% or greater. This allows you to exclude accidental effects on the final result.

If the probability is less than 95%, then it is necessary to increase the number of analyzed cases. If increasing the sample does not help, then we must admit that reliable result in this case it is difficult to achieve.

2) Probability of error. Parameter denoted by a Latin letter p(p-value).

p- the probability of error in obtaining a reliable result. It is calculated in fractions of one. To convert to a percentage, multiply by 100. Three commonly used values are commonly cited in clinical trial reports: p:

p > 0.05 - NOT statically significant (that is, the probability of error is greater than 5%),
p< 0.05 - является статистически значимым (вероятность ошибки 5% и меньше),
p< 0.01 - высокая статистическая значимость (вероятность ошибки не выше 1%).

You are now able to understand most of the findings in scientific medical journal publications. Practice:

A multicenter, randomized, prospective, open-label study with blinded endpoint assessment was conducted. ... A significant decrease in the insulin sensitivity index was obtained after 16 weeks of treatment compared to the initial values in both the moxonidine group (p = 0.02) and the metformin group (p = 0.03). There were no significant differences in this indicator between the study groups (p = 0.92).

Today, a large number of international clinical trials of drugs are taking place in Russia. What does this give to 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 MedNews.

Tatiana Serebryakova. Photo: from personal archive

What path does a medicine take from the moment it is invented until it reaches the market? pharmacy chain?

— 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 during a preclinical study any risks are identified, for example, teratogenicity (the ability to cause congenital deformities), then such a drug will not be used.

It was the lack of research that led to the dire consequences of using the drug Thalidomide in the 50s of the last century. Pregnant women who took it gave birth to children with deformities. This shining example, which is given in all textbooks on clinical pharmacology and which pushed the whole world to strengthen control over the introduction of new drugs to the market, making it mandatory to conduct a full-fledged research program.

Clinical trials consist of several phases. The first, as a rule, involves healthy volunteers, which confirms the safety of the drug. The second phase evaluates the drug's effectiveness in treating the disease in a small number of patients. In the third, their number expands. And if research results show that the drug is effective and safe, it can be registered for use. The Ministry of Health is involved in this.

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

The production of the drug begins at the research stage - in small quantities - and is scaled up after registration. The production of one drug may involve several factories located in different countries Oh.

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 ensure that the drug is as safe and effective for Russian patients as for study participants in other countries. The fact is that the effects of a drug can vary in different populations and regions, depending on various factors (genotype, treatment resistance, standards of care).

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

Are the principles of conducting clinical trials in Russia somehow different from those accepted in world practice?

— All clinical trials taking place 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 carried out in accordance with a protocol (detailed instructions for conducting a study), uniform for all countries and mandatory for all research centers participating in it. The same study could involve both the UK and South Africa, and Russia, and China, and the USA. 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 truly effective and safe?

“That’s why they are held.” The research protocol determines, among other things, statistical methods for processing the information received and the number of patients required to obtain statistically reliable results. In addition, a conclusion about the effectiveness and safety of a drug cannot be given based on the results of only one study. As a rule, a whole program of complementary research is carried out - on different categories patients in different age groups.

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

Who has the right to conduct clinical research?

— When planning a study, the manufacturing company must obtain permission to conduct it in a specific country. In Russia, such permission is issued by the Ministry of Health. He also maintains a special register of accredited medical institutions for conducting 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 its research. The list of centers selected to conduct a specific study also requires approval from the Ministry of Health.

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

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

Who pays for the research?

— The drug manufacturing company. It acts as the customer of the research and, in accordance with legal norms, pays the costs of its implementation to research centers.

And who controls their quality?

— Good clinical practice (GCP) requires that all studies are conducted according to standard rules to ensure quality. Their compliance is monitored by different levels. It is the legal responsibility of the research center itself to ensure proper quality in the conduct of research, and this is controlled by the appointed principal investigator. The manufacturing company, for its part, monitors the research, 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 own inspections, monitoring compliance with requirements by accredited centers. This 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 reliable results. If, due to a poorly conducted study, patients' health deteriorates after using the drug, this could result in litigation and multimillion-dollar fines.

During the research process, a new drug is tested in humans. How dangerous is this?

"Pregnant Alison Lapper" (sculptor Marc Quinn). Artist Alison Lapper is one of the most famous victims of phocomelia. birth defect associated with maternal use of thalidomide during pregnancy. Photo: Gallery/Flickr

— There is danger always and everywhere. But a new drug is 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 risks for participants; first, the drug is tested on a small group. There are also strict patient selection criteria. All study participants 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 treatment with the study 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 and receive payment for their participation. But it must be said that the moral and ethical side is of particular importance for volunteers, the understanding that by their participation in research they are helping sick people.

How can a sick person take part in research on new drugs?

— If a patient is being treated in a clinic where the study is being conducted, then most likely he will be offered to become a participant. 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-oncology drug are currently underway in Russia. More than 300 accredited research centers across the country participate. We have specially opened a “hotline” (+7 495 916 71 00, ext. 391), through which doctors, patients and their relatives can obtain 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 (GCP). GCP stages

The process of creating new medicines is carried out in accordance with the international standards of GLP (Good Laboratory Practice), GMP (Good Manufacturing Practice) and GCP (Good Clinical Practice).

Clinical drug trials involve the systematic study of an investigational drug in humans to test its therapeutic effect or identifying an adverse reaction, as well as studying absorption, distribution, metabolism and excretion from the body to determine its effectiveness and safety.

Clinical trials of a drug are a necessary stage in the development of any new drug, or the 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 so-called preclinical studies, the purpose of which is to obtain scientific estimates and evidence of the effectiveness and safety of drugs. 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.

A clinical study (test) of a medicinal product is a systemic study of a medicinal product through its use in humans (patient or healthy volunteer) in order to assess its safety and effectiveness, as well as to identify or confirm its clinical, pharmacological, pharmacodynamic properties, assess absorption, distribution, metabolism, excretion and interaction with other drugs. The decision to initiate a clinical trial is made by the customer, who is responsible for organizing, monitoring and financing the trial. Responsibility for the practical conduct of the research rests with the researcher. 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, GСP (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 of voluntary informed consent (IS), obtained after a detailed review of the study materials. Patients (volunteers) participating in a trial of a new drug must receive information about the nature and possible consequences tests, the expected effectiveness of the drug, the degree of risk, enter into an agreement on life and health insurance in the manner prescribed by law, and during the tests be under constant supervision of qualified personnel. In the event of a threat to the health or life of the patient, as well as at the request of the patient or his legal representative, the director of the clinical trial is obliged to suspend the trial. In addition, clinical trials are suspended if a drug is unavailable or insufficiently effective, or if ethical standards are violated.

The first stage of clinical trials of the drug is carried out on 30 - 50 volunteers. The next stage is expanded trials on the basis of 2 - 5 clinics involving a large number (several thousand) of patients. At the same time, individual cards of patients with detailed description results of various studies - blood tests, urine tests, ultrasound, etc.

Each drug undergoes 4 phases (stages) of clinical trials.

Phase I. First experience of using a new active substance in humans. Most often, studies begin with volunteers (healthy adult men). The main goal of the research is to decide whether to continue working on a new drug and, if possible, to establish the doses that will be used in patients during phase II clinical trials. During this phase, researchers obtain preliminary data on the safety of the new drug and describe its pharmacokinetics and pharmacodynamics in humans for the first time. Sometimes it is not possible to conduct phase I studies in healthy volunteers due to the toxicity of the drug (treatment oncological diseases, AIDS). In this case, non-therapeutic studies are carried out with the participation of patients with this pathology in specialized institutions.

Phase II. This is usually the first experience of use in patients with the disease for which the drug is intended to be used. The second phase is divided into IIa and IIb. Phase IIa are therapeutic pilot studies because the results obtained from them provide optimal planning for subsequent studies. Phase IIb studies are larger studies in patients with the disease that is the primary indication for the new drug. The main goal is to prove the effectiveness and safety of the drug. The results of these studies (pivotal trial) serve as the basis for planning phase III studies.

Phase III. Multicentre trials involving large (and, if possible, diverse) patient groups (average 1000-3000 people). The main goal is to obtain additional data on safety and effectiveness various forms the drug, the nature of the most common adverse reactions, etc. Most often, clinical studies of this phase are double-blind, controlled, randomized, and the research conditions are as close as possible to normal real routine medical practice. Data obtained in phase III clinical trials are the basis for creating instructions for the use of the drug and for deciding on its registration by the Pharmacological Committee. Recommendation for clinical application in medical practice it is considered justified if a new drug:

- more effective than known drugs of similar action;
- has better tolerability than known drugs (with the same effectiveness);
- effective in cases where treatment known drugs unsuccessfully;
- more economically profitable, has more simple technique treatment or more convenient dosage form;
- at combination therapy increases the effectiveness of existing drugs without increasing their toxicity.

Phase IV. Research is carried out after the drug is marketed in order to obtain more detailed information about long-term use in different groups of patients and with various factors risk, etc. and thus more fully evaluate the drug strategy. Participates in the study a large number of patients, this makes it possible to identify previously unknown and rare adverse events.

If a drug is going to be used for a new indication that has not yet been registered, then additional studies are conducted, starting with phase II. Most often in practice, an open study is carried out, in which the doctor and the patient know the method of treatment (the study drug or a comparison drug).

When testing with a single-blind method, the patient does not know which drug he is taking (it may be a placebo), and when using a double-blind method, neither the patient nor the doctor is aware of this, but only the leader of the trial (in a modern clinical trial of a new drug, four parties: the sponsor of the study (most often this is a pharmaceutical manufacturing company), the monitor - a contract research organization, a doctor-researcher, a patient). In addition, triple-blind studies are possible, when neither the doctor, nor the patient, nor those who organize the study and process its data know the assigned treatment for a particular patient.

If doctors know which patient is being treated with which drug, they may spontaneously evaluate treatment based on their preferences or explanations. The use of blind methods increases the reliability of the results of a clinical trial, eliminating the influence of subjective factors. If the patient knows that he is receiving a promising new drug, the effect of treatment may be associated with his reassurance, satisfaction that the most desired treatment possible has been achieved.

Placebo (Latin placere - to like, to appreciate) means a drug that obviously does not have any healing properties. The Large Encyclopedic Dictionary defines placebo as “a dosage form containing neutral substances. Used to study the role of suggestion in therapeutic effect any medicinal substance, as a control when studying the effectiveness of new drugs." test quality medicine drug

Negative placebo effects are called nocebo. If the patient knows what side effects are present in the drug, then in 77% of cases they occur in him when he takes a placebo. Belief in a particular effect can cause side effects to appear. According to the commentary of the World Medical Association to Article 29 of the Declaration of Helsinki, “...the use of placebo is justified if it does not lead to an increased risk of causing serious or irreversible harm to health...”, that is, if the patient is not left without effective treatment.

There is a term for “completely blinded studies” when all parties to the study are blinded to the type of treatment being given to a particular patient until the results are analyzed.

Randomized controlled trials serve as the standard of quality for scientific research into the effectiveness of treatments. The study first selects patients from a large population of people with the condition being studied. These patients are then randomly divided into two groups matched according to the main prognostic features. Groups are formed randomly (randomization) using tables of random numbers in which each digit or each combination of digits has an equal probability of selection. This means that patients in one group will, on average, have the same characteristics as patients in another. In addition, before randomization, it should be ensured that disease characteristics known to have a strong influence on outcome occur at similar rates in the treatment and control groups. To do this, you must first distribute patients into subgroups with the same prognosis and only then randomize them separately in each subgroup - stratified randomization. The experimental group (treatment group) receives an intervention that is expected to be beneficial. The control group (comparison group) is in exactly the same conditions as the first group, except that its patients are not exposed to the intervention being studied.

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

History of origin legislative framework clinical trials

In the narrowest sense evidence-based medicine is a method of medical clinical practice, when a medical practitioner applies to a patient only those methods of prevention, diagnosis and treatment, the usefulness and effectiveness of which has been proven in studies performed at a high methodological level, and ensures an extremely low probability of obtaining “random 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 insufficiently studied drugs. One of the most resonant cases was the death of 107 children in 1937, when the M. E. Massengill company used sulfonamide (at that time the most effective remedy fight against infections, in fact, the first synthetic antiseptic) diethylene glycol (a toxic solvent that 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 claimed more than a hundred lives, which prompted the US authorities to pass a law on mandatory testing of drugs 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 thalidomide tragedy that occurred in the late 50s and early 60s. During tests on animals, in particular mice, the drug showed exceptional results and did not reveal any side effects, including in offspring. When the drug was used in pregnant women as a remedy against insomnia and toxicosis, it led to the birth of more than 10,000 children around the world with defects of long bones and limbs. After this, it became obvious that full tests and studies must be carried out, and the experience of individual specialists cannot be a sufficient basis for registering the drug.

The first laws establishing government control over the production of drugs were adopted in Europe back in 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 as ICH), which became the basis for local regulations since 1996/97 in the USA , Japan and the EU, and since 2003 introduced by Order of the Ministry of Health of the Russian Federation No. 266 in Russia (hereinafter referred to as GOST R 52379-2005 “Good Clinical Practice”).

The most common myths about conducting clinical trials:

1. test new ones in public secretly

Today, when conducting research, we strictly follow the letter of the law, that is, the ICH document, according to which patients cannot be exposed to unreasonable risks, their rights and confidentiality of personal information are respected, scientific interest, as well as the interests of society, cannot prevail over the safety of patient participants in the study, These studies are scientifically sound and verifiable. “Compliance with this standard provides assurance to society that the rights, safety and welfare of research subjects are protected, are consistent with the principles set forth in the WMA Declaration of Helsinki, and that clinical trial data are reliable.” Few people are as protected in this process as the patient involved. In addition, before any procedure required by the study protocol is performed, the patient receives full information about the study, possible risks and inconveniences, procedures and examinations within the study, study drugs, the likelihood of being included in a particular treatment group, learns about the availability alternative ways treatment of his disease, is notified of his 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 person’s desire to participate in the study. If something is not clear to the patient, the doctor is obliged to provide additional explanations about the study being conducted. 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

Firstly, regarding the low cost of research in developing countries, this is not an entirely correct statement. If we take Russia, which many experts classify as a developing market, then the cost of conducting clinical trials of drugs in our country approaches and sometimes exceeds the price level in Europe and the United States, 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 costs for logistics, as well as for the payment of customs duties and taxes imposed on drugs and other research materials imported into Russia.

Secondly, research in developing countries requires much more attention and control from companies, which makes the whole process more complex. 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 make additional investments in training clinical 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 receive 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 ICH GCP in order to subsequently have the right to register the drug in the USA, EU and other developed countries.

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

First, let's understand the phases of any clinical trial. After preclinical studies and testing of the drug on biological models and animals, the so-called phase I begins - the first trial in humans, which is generally aimed at assessing the tolerability of the drug in the human body, and 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 will participate in the study. As has already been said, subject to research being carried out in developing countries, for many people there this is the only chance to receive at least some treatment. Phase II involves the participation of several hundred patients suffering from the specific disease for which the drug being studied is intended to treat. The main task of phase II is to select the most appropriate therapeutic dose of the study drug. And phase III is a pre-registration study involving 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 studies are one of the most dangerous moments of the entire 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 everything necessary equipment and trained medical staff so that if something goes wrong, you can always react quickly. Most often, these studies are carried out in the USA, Canada and Holland, and in some countries they are limited or completely prohibited due to their unpredictability, such as in India and Russia (we have a ban on the study of foreign drugs with the participation of 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 during a clinical trial as the patient participating in it. It should not be forgotten that the main principles of research with human participants to this day remain voluntary participation and non-harm. All medical procedures are performed only if the person is fully informed and with his consent. This is regulated by the already mentioned Declaration of Helsinki and ICH GCP. The protocol for any clinical trial (and this is the main document), without which the research is impossible and which must be approved and approved by the Ministry of Health, regulates the interaction of the doctor with the patient, including necessarily indicating that the doctor provides all information in full necessary information and is responsible for the balance of benefit and risk for the study participant.

All patients participating in a clinical trial are under close medical supervision and regularly undergo various examinations, including the most expensive ones, at the expense of the company conducting the trial; everything and any medical events, changes in health status are recorded and studied, and if adverse events develop, even those not related to the study drug, they are immediately received adequate treatment. Patients participating in clinical trials, on the other hand, are in better conditions health control compared to others.

The process also involves third-party observers from among the employees of the customer company or contract research organization, who monitor its progress, and if the doctor suddenly violates established order or exceeds their authority, may initiate severe punishment, including stopping the study.

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

It should be remembered that a placebo is an inactive substance that is solely external signs(in appearance, taste, etc.) is indistinguishable from the drug under study, so, in fact, it cannot affect the human body in any way. However, for ethical reasons, the use of placebo in clinical trials is limited in accordance with the principles of the Declaration of Helsinki. According to them, the benefits, risks, disadvantages and effectiveness of a new treatment must be assessed in comparison with the best available treatments. The exception is when the use of placebo in research is justified because effective way There is no cure for the disease, or there are compelling scientifically proven reasons for using a placebo to evaluate the effectiveness or safety of the treatment being studied. In any case, patients receiving placebo should not be at risk of serious or irreversible harm to their health. In addition, the patient participating in a clinical trial is under the careful supervision of highly qualified specialists and has access to the most modern drugs and technologies, which makes the risks minimal.

6. Clinical trials are an excessive measure. To release a drug to the market, information obtained during preclinical testing of the drug on biological models and animals is sufficient.

If this were true, pharmaceutical companies would have long ago stopped spending billions of dollars on human research. But the whole point is that there is no other way to understand how this or that drug affects a person except to conduct an experiment. It is necessary to understand that the situation simulated during 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 concomitant diseases in the anamnesis. Or how the drug will act on the human body in different dosage how it will be combined with other drugs. All this requires research with human participants.

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

Drug 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 carefully monitored by government 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 hit the market and will not bring profit to the company. So careful monitoring of the research is, first of all, the interest of the customer company.

7. In Russia, many untested medicines are sold in pharmacies; only foreign countries conduct thorough research before introducing 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 involves the analysis of documents submitted by the company developing the drug, including those on conducting clinical trials, by special expert bodies - on the one hand, clinical pharmacologists, and on the other hand, by the Ethics Council specially created under the Ministry of Health of the Russian Federation. The fundamental point is the collegiality of decisions and the competence of persons making an independent decision. And the procedure for making a decision based on the results of clinical studies, which are reviewed by experts from the Ministry of Health of the Russian Federation for the completeness and quality of the studies performed, and achieving the main goal - obtaining evidence of the effectiveness and safety of using the drug for its intended purpose, is also strictly regulated. It is at this stage that it is decided whether the results obtained are sufficient for registration of the drug or whether additional research is required. Russian legislation Today, in terms of the level of requirements for conducting and evaluating the results of clinical trials, it is not inferior to the regulations of the leading countries of the world.

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

This is extremely important stage 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 effectiveness of the drug on a sufficiently large population over a long period of time and in “real-life conditions”. The fact is that 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 assessing before registration how the drug will behave in patients with different concomitant diseases, in elderly patients, in patients taking a wide range of other medications. 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 recorded simply because they were not encountered 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 goes on sale, we must closely monitor its fate in order to evaluate and study the most important parameters of drug therapy, such as interactions with other drugs, effects on the body during 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 this data is 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 a drug reveals previously unknown dangerous side effects, its use may be limited, including suspension and revocation of registration.