Pharmacology Analytics

Clinical trials of drugs: myths and reality

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

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

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

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 As a result, when it became clear that the drug was deadly, it was withdrawn from sale as quickly as possible, but by that time it had managed to claim more than a hundred lives, which prompted the US authorities to pass a law on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

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

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

The most common myths about conducting clinical trials

1. Pharmaceutical companies are testing new drugs on people in secret.

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Clinical Research are referred to as "... any study involving human subjects, which has the purpose of identifying or testing the clinical, pharmacological and / or pharmacodynamic properties of one or more investigational medicinal products, and / or adverse reactions to one or more medicinal products and / or studying absorption, distribution, metabolism and excretion of one or more medical products in order to confirm its (their) safety and / or effectiveness. (EU directive)

The requirements for planning and conducting clinical trials (CTs) are formulated in the Good Clinical Practice (GCP) standards. Following the GCP rules ensures the accuracy of the data obtained and respect for the rights of patients. These rules apply to all clinical trials, regardless of whether it is carried out by a pharmaceutical company or research doctors as part of their dissertations, whether new drugs, new methods of treatment, new medical equipment or medical devices, including dental materials, are being investigated.

Clinical trials are conducted in 4 phases (Fig. 9.2).

Rice. 9.2. The scheme of creating a new drug and the phase of CI (the indicated time intervals are conditional)

Phase I clinical trials represents the first experience of using a new active substance in humans. It is carried out with the participation of a small number of healthy volunteers (average 10-20 adult men). The main goals of this phase are to determine the highest tolerated dose, identify adverse events, study pharmacodynamics and pharmacokinetics, and decide on the meaning of continuing further work on a new drug.

In Phase II clinical trials the first controlled trials (see below) of drugs are being conducted in a small number (100-300) of patients with the disease for which they are planned to be used. The main goals of phase II are confirmation of the therapeutic effect, selection of an effective dose and dosing regimen, as well as further assessment of the tolerability of a new drug.

PhasesIII clinical trials are multicentre controlled trials involving large (and possibly diverse) groups of patients. Typically, 1000-3000 patients are involved in this phase. The main objectives of phase III trials are to obtain additional evidence of the efficacy and safety of various forms of a new drug, therapeutic and pharmacoeconomic advantages over drugs of similar action, to identify the most common adverse effects and possible interactions with other drugs.

After the successful completion of phase III, the manufacturing company of the new drug submits documents to the appropriate authority for registration of the drug and obtaining permission for industrial production and use in clinical practice (Fig. 9.3). In our country, the examination and registration of drugs is within the competence of the Ministry of Health of the Russian Federation and is carried out by the State Scientific Center for Expertise of Medicinal Products, the Pharmacological and Pharmacopeial Committees.

Figure 9.3. Registration scheme for a new medicinal product in Russia

Phase IV clinical trials (post-registration) carried out after the start of the sale of the drug. Their goal is to obtain more detailed information about the use of a new drug in different groups of patients, in the presence of various risk factors. In phase IV, new, previously unknown undesirable effects are often revealed, the tactics of using a new agent in clinical practice are specified.

Any drug can be prescribed only according to registered indications. In the case when, in the process of using a drug or in the course of scientific research, proposals arise for a new indication for its use, it is necessary to conduct additional trials, starting from Phase II, to register this indication.

Implementation of the strict requirement of modern pharmacotherapy - the minimum dose of the drug to ensure the optimal therapeutic effect without side effects - is possible only with a thorough study of new drugs at the preclinical and clinical stages.

Preclinical (experimental) study of biologically active substances is conventionally divided into pharmacological and toxicological. These studies are interdependent and are based on the same scientific principles. The results of studying the acute toxicity of a potential pharmacological substance provide information for subsequent pharmacological studies, which in turn determine the extent and duration of the study of chronic toxicity of the substance.

The purpose of pharmacological research is to determine the therapeutic efficacy of the product under study - the future medicinal substance, its effect on the main body systems, as well as to establish possible side effects associated with pharmacological activity.

It is very important to establish the mechanism of action of a pharmacological agent, and if available, non-main types of action, as well as possible interactions with other drugs.

Pharmacological studies are carried out on models of relevant diseases or pathological conditions using single, constantly increasing doses of substances in order to find the desired effect. Data from initial pharmacological studies can already give some insight into the toxicity of a substance, which should be deepened and expanded in special studies.

In toxicological studies of a pharmacological agent, the nature and severity of a possible damaging effect on the body of experimental animals is established. There are four stages of research.

1. The study of the main type of pharmacological activity in several experimental models in animals, as well as the establishment of the pharmacodynamics of the drug.

2. Study of the acute toxicity of the agent with a single application of DL50max / DE50min. If this coefficient is equal to 1 or the effective dose for a person.

3. Determination of the chronic toxicity of the compound, which is the internal organs, brain, bones, eyes.

4. Establishment of specific toxicity of pharmacological action).

Identification of the damaging effect of the test agent on the body of experimental animals gives researchers information about which organs and tissues are most sensitive to a potential drug and what should be paid special attention to during clinical trials.

The study of new pharmacological agents in animals is based on data on the existence of a certain correlation between the effect of these compounds on animals and humans, whose physiological and biochemical processes are largely similar. Due to the fact that there are significant species differences between animals in the intensity of metabolism, the activity of enzyme systems, sensitive receptors, etc., studies are carried out on several animal species, including cats, dogs, monkeys, which are phylogenetically closer to the person.

It should be noted that a similar scheme for conducting laboratory (experimental) studies is acceptable for both a simple and a complex drug, in the experiment with which mandatory additional biopharmaceutical studies are planned, confirming the optimal choice of the type of dosage form and its composition.

An experimental preclinical study of a new agent (its pharmaceutical, pharmacological and toxicological properties) is carried out according to standard unified methods, which are usually described in the guidelines of the Pharmacological Committee, and must meet the requirements of Good Laboratory Practice (GLP) -- Good Laboratory Practice (GLP) ).

Preclinical studies of pharmacological substances make it possible to develop a scheme for rational testing of drugs in a clinic, to improve their safety. Despite the great importance of preclinical studies of new substances (drugs), the final judgment on their effectiveness and tolerability is formed only after clinical trials, and often after a certain period of their widespread use in medical practice.

Clinical trials of new drugs and preparations should be carried out with the maximum observance of the requirements of the international standard "Good Clinical Practice" (Good Clinical Practice (GCP)), which regulates the planning, conduct (design), monitoring, duration, audit, analysis, reporting and documentation of research.

When conducting clinical trials of medicinal preparations, special terms are used, the content of which has a certain meaning. Consider the main terms adopted by the GCP.

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

Investigational product is the pharmaceutical form of the active substance or placebo being studied or used for comparison in a clinical trial.

Sponsor (customer) - an individual or legal entity that assumes responsibility for the initiative, management and / or financing of clinical trials.

Investigator -- the person responsible for conducting a clinical trial.

The subject of the test is a person participating in clinical trials of an investigational product.

Clinical Trial Quality Assurance is a set of measures to ensure that trials comply with GCP requirements based on general and professional ethics, standard operating procedures and reporting.

To conduct clinical trials, the manufacturer produces a certain amount of the drug, controls its quality in accordance with the requirements laid down in the VFS project, then it is packaged, labeled (indicated "For clinical trials") and sent to medical institutions. Simultaneously with the medicinal product, the following documentation is sent to the clinical sites: submission, decision of the SNETSLS, clinical trials program, etc.

The decision to conduct clinical trials from a legal point of view and their ethical justification is based on an assessment of experimental data obtained in animal experiments. The results of experimental, pharmacological and toxicological studies should convincingly testify to the advisability of testing a new drug in humans.

In accordance with existing legislation, clinical trials of a new drug are carried out on patients suffering from the diseases for which the drug is intended to be treated.

The Ministry of Health approved methodological recommendations for the clinical study of new drugs belonging to various pharmacological categories. They are developed by leading scientists of medical institutions, discussed and approved by the Presidium of the GNETSLS. The application of these recommendations ensures the safety of patients and contributes to the improvement of the level of clinical trials.

Any study on humans should be well organized and carried out under the supervision of specialists. Incorrectly conducted tests are recognized as unethical. In this regard, much attention is paid to the planning of clinical trials.

In order to prevent narrow professional interests from manifesting in the work of doctors, which do not always meet the interests of the patient and society, and also in order to ensure human rights, in many countries of the world (USA, Great Britain, Germany, etc.) special ethical committees have been created to supervise scientific drug research in humans. An ethical committee has also been created in Ukraine.

International acts on the ethical aspects of conducting medical research on people have been adopted, for example, the Nuremberg Code (1947), which reflects the protection of human interests, in particular, the inviolability of his health, as well as the Declaration of Helsinki (1964), which contains recommendations for physicians on biomedical research in humans. The provisions set forth in them are advisory in nature and at the same time do not exempt from criminal, civil and moral responsibility provided for by the laws of these countries.

The medical and legal foundations of this system guarantee both safety and timely adequate treatment of patients, as well as providing society with the most effective and safe medicines. Only on the basis of official trials, methodically correctly planned, objectively assessing the condition of patients, as well as scientifically analyzed experimental data, can correct conclusions be drawn about the properties of new drugs.

Clinical trial programs for different pharmacotherapeutic groups of drugs may differ significantly. However, there are a number of basic provisions that are always reflected in the program: a clear formulation of the goals and objectives of the test; defining selection criteria for testing; an indication of the methods of distribution of patients in the test and control groups; number of patients in each group; method for establishing effective doses of the medicinal product; the duration and method of testing the controlled drug; an indication of the comparator and/or placebo; methods for quantifying the effect of the drug used (indicators subject to registration); methods of statistical processing of the obtained results (Fig. 2.3).

The program of clinical trials undergoes a mandatory review by the Ethics Commission.

Patients (volunteers) participating in the trial of a new drug must receive information about the essence and possible consequences of the trials, the expected effectiveness of the drug, the degree of risk, conclude a life and health insurance contract in the manner prescribed by law, and during the trials be under the 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 head of clinical trials is obliged to suspend the trials. In addition, clinical trials are suspended in case of lack or insufficient effectiveness of the drug, as well as violation of ethical standards.

Clinical testing of generic drugs in Ukraine is carried out under the "Limited Clinical Trials" program to establish their bioequivalence.

In the course of clinical trials, drugs are divided into four interrelated phases: 1 and 2 - pre-registration; 3 and 4 - post-registration.

The first phase of the study is carried out on a limited number of patients (20-50 people). The goal is to establish the tolerance of the drug.

The second phase is for 60-300 patients in the presence of the main and control groups and the use of one or more reference drugs (standards), preferably with the same mechanism of action. The goal is to conduct a controlled therapeutic (pilot) study of the drug (determining the ranges: dose - mode of application and, if possible, dose - effect) for optimal provision of further trials. The evaluation criteria are usually clinical, laboratory and instrumental indicators.

The third phase is for 250-1000 people and more. The goal is to establish a short-term and long-term balance between safety and efficacy of the drug, to determine its overall and relative therapeutic value; to study the nature of the occurring adverse reactions, factors that change its action (interaction with other drugs, etc.). Tests should be as close as possible to the expected conditions of use of this medicinal product.

The results of the clinical trial are recorded in the individual standard card of each patient. At the end of the test, the results obtained are summed up, statistically processed and drawn up in the form of a report (in accordance with the requirements of the GNETSLS), which ends with reasoned conclusions.

A report on clinical trials of a medicinal product is sent to the State Scientific and Clinical Medical Center, where it undergoes a thorough examination. The end result of the examination of all the materials received by the State Scientific and Medical Center for Drugs and Drugs is an instruction for the use of a medicinal product that regulates its use in a clinical setting.

A drug can be recommended for clinical use if it is more effective than known drugs of a similar type of action; has a better tolerability compared to known drugs (with the same efficiency); effective in conditions where the use of existing drugs is unsuccessful; more economically advantageous, has a simpler method of application or a more convenient dosage form; in combination therapy, it increases the effectiveness of existing drugs without increasing their toxicity.

The fourth phase (post-marketing) research is carried out on 2000 or more people after the approval of the medicinal product for medical use and industrial production (after the drug is received by the pharmacy). The main goal is to collect and analyze information about side effects, evaluate the therapeutic value and strategies for prescribing a new drug. Studies in the fourth phase are carried out on the basis of information in the instructions for use of the drug.

When conducting clinical trials of new drugs, the most important task is to ensure their quality. To achieve this goal, monitoring, auditing and inspection of clinical trials is carried out.

Monitoring is the activity of control, observation and verification of a clinical trial carried out by a monitor. The monitor is a trustee of the organizer of clinical trials (sponsor), who is responsible for directly monitoring the progress of the study (correspondence of the data obtained with the protocol data, compliance with ethical standards, etc.), assisting the researcher in conducting the trial, ensuring his relationship with the sponsor.

Audit is an independent verification of a clinical trial, which is carried out by services or persons not participating in it.

The audit can also be carried out by representatives of the state authorities responsible for the registration of medicines in the country. In these cases, the audit is called an inspection.

Working in parallel to achieve a common goal, the monitor, auditors and official inspectors ensure the required quality of clinical trials.

When conducting clinical trials involving a large number of patients, there is a need for prompt processing of the results of the study. For this purpose, the Pfizer Corporation has developed new informatics methods (the Q-NET computer program for processing the database obtained during the study of the Viagra drug), which makes it possible to get acquainted within a day with the results of clinical trials involving 1450 patients who are held in 155 clinical centers located in various countries. The creation of such programs allows minimizing the time for promoting new drugs at the stage of clinical trials.

Thus, the effectiveness and safety of medicines is guaranteed:

· clinical trials;

· post-marketing clinical trials for widespread medical use of drugs;

· careful examination of the results at all the above stages.

The presence of a comprehensive assessment of the efficacy and safety of drugs and extrapolation of the results at three stages makes it possible to identify the mechanisms of possible side effects, the level of drug toxicity, and also to develop the most optimal schemes for its use.

The prospect of an integrated approach is emerging, based on the optimal combination of the principles of biopharmacy, the latest achievements in chemical and pharmaceutical technologies, with a wide involvement of clinical experience in the creation and production of new drugs. Such an approach to this problem is qualitatively new in pharmaceutical practice and, obviously, will open up new possibilities in the complex process of creating and using drugs.

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

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

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

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

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

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

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

Types of clinical studies:

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

There are no alternative research methods comparable in their effectiveness;

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

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

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

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

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

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

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

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

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

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

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

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

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

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

1) minors without parents;

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

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

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

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

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