Clinical trials. Profession: Specialist in drug clinical trials. What is GCP Protocol

Now in the world there are a huge number of drugs, for almost all existing diseases. The development of a new drug is not only time-consuming but also expensive. After the medicine is created, it is necessary to test how it acts on the human body, how effective it will be. For this purpose, clinical studies are being carried out, which we will talk about in our article.

Clinical research concept

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

But animals are different from humans, so how experimental mice react to the drug does not at all mean getting the same reaction in humans.

If we give a definition of what clinical trials are, then we can say that this is a system of using various methods to find out the safety and effectiveness of a drug for humans. In the course of studying the drug, all the nuances are clarified:

  • Pharmacological effects on the body.
  • Suction speed.
  • Bioavailability of the drug.
  • Withdrawal period.
  • Features of metabolism.
  • Interaction with other medications.
  • Safety for humans.
  • Manifestation of side effects.

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

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

Research statistics

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

According to one of the American drug manufacturers' associations, out of 10 thousand investigational drugs, only 250 reach the preclinical stage, as a result, clinical trials will be carried out only for about 5 drugs, and 1 will reach mass production and registration. These are the statistics.

Laboratory research goals

Research on any drug has several goals:

  1. Establish how safe this drug is for humans. How the body will tolerate it. For this, volunteers are found who agree to participate in the research.
  2. In the course of the study, the optimal doses and treatment regimens are selected to obtain the maximum effect.
  3. To establish the degree of drug safety and its effectiveness for patients with a specific diagnosis.
  4. Study of unwanted side effects.
  5. Consider expanding drug use.

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

Research classification

An issue like the classification of drug studies can be approached from different angles. Depending on the factor, the types of research can be different. Here are some ways to classify:

  1. By the degree of interference in the tactics of patient management.
  2. Research can differ in its objectives.

In addition, there are also types of laboratory tests. Let us examine this issue in more detail.

Varieties of Patient Intervention Studies

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

  1. Observational. In the course of such a study, no interference occurs, information is collected and the natural course of all processes is monitored.
  2. Research without intervention or non-interventional. In this case, the drug is prescribed according to the usual scheme. In the research protocol, the issue of attributing the patient to any treatment tactics is not decided in advance. Prescribing is clearly separated from patient enrollment. The patient does not undergo any diagnostic procedures, the data is analyzed using epidemiological methods.
  3. Interventional research. It is carried out when it is necessary to study still unregistered drugs or to find out new directions in the use of known drugs.


Classification criterion - research objective

Depending on the purpose, general clinical trials can be:

  • Preventive. They are carried out with the aim of finding the best ways to prevent diseases in a person that he has not previously suffered or to prevent relapse. Usually, vaccines, vitamin preparations are studied in this way.
  • Screening tests allow you to find the best method for detecting diseases.
  • Diagnostic studies are carried out to find more effective ways and methods for diagnosing the disease.
  • Therapeutic research provides an opportunity to study the effectiveness and safety of drugs and therapy methods.

  • Quality of life research is being conducted to understand how the quality of life of people with certain conditions can be improved.
  • Expanded access programs involve the use of an experimental drug in patients with life-threatening diseases. Usually such drugs cannot be included in laboratory tests.

Research types

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

  • A pilot study is being conducted to collect the necessary data for the next stages of drug study.
  • Randomized assignment of patients is randomly assigned to groups, and they have the opportunity to receive both the study drug and the control drug.

  • A controlled study of a drug is investigating a drug whose safety is not yet known. It is compared with an already well-researched and well-known drug.
  • An uncontrolled study does not imply a control group of patients.
  • A parallel study is carried out at once in several groups of patients who receive the study drug.
  • In crossover studies, each patient receives both drugs, which are compared.
  • If the study is open, then all its participants know the drug that the patient is taking.
  • Blind or disguised learning involves two parties who are unaware of patient grouping.
  • A prospective study is conducted with patients assigned to groups whether or not they receive the study drug before outcomes occur.
  • In retrospective, the outcomes of studies that have already been conducted are considered.
  • A clinical research center can be involved in one or several, depending on this, there are single-center or multicenter studies.
  • In a parallel study, the results of several groups of subjects are compared at once, among which one is a control, and two or more others receive the study drug.
  • Similar case studies involve comparing patients with a specific disease with those without such a disease in order to identify a relationship between outcome and prior exposure to certain factors.

Research stages

After the production of a medicinal product, he must go through all the studies, and they begin with preclinical ones. Carried out on animals, they help the pharmaceutical company understand whether it is worth investigating the drug further.

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

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

Phase one

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

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

  • How the drug is tolerated by humans.
  • Pharmacological properties.
  • Period of absorption and excretion from the body.
  • Preliminarily assess the safety of its reception.

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

  1. The use of single increasing doses of the drug. The first group of subjects is injected with a certain dose of the drug, if it is well tolerated, then the next group the dosage is increased. This is done until the intended safety levels are reached or side effects begin to appear.
  2. Studies of multiple escalating doses. A group of volunteers receives a small drug several times, after each receipt, tests are taken, and the behavior of the drug in the body is assessed. In the next group, an increased dose is repeatedly administered and so on up to a certain level.

Second phase of research

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

The main goal at this stage of drug study is to determine the required dosage and therapy regimen. The amount of medication given to patients in this phase is slightly lower than the highest doses given to subjects in the first phase.

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

Phase 3 research

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

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

After the drug at this stage confirms its safety and effectiveness, a registration dossier is prepared. It contains information on the results of the study, the composition of the medicine, the shelf life and storage conditions.

Phase 4

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

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

Research protocol

Any research protocol should contain the following information:

  • The purpose of the study of the drug.
  • The tasks that the researchers set themselves.
  • Study design.
  • Study methods.
  • Statistical questions.
  • Organization of the study itself.

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

After the study is completed, the protocol is the document against which auditors and inspectors can verify it.

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

Clinical trial / study: Any research / trial conducted with a human subject to identify or confirm the clinical and / or pharmacological effects of investigational drugs and / or detect adverse reactions to investigational drugs, and / or study their absorption, distribution, metabolism and excretion in order to perform safety and / or efficacy assessments.

The terms "clinical trial" and "clinical research" are synonymous.

A source: Rules of Good Clinical Practice of the Eurasian Economic Union

Clinical study of a medicinal product- study of the diagnostic, therapeutic, prophylactic, pharmacological properties of the medicinal product in the process of its use in humans, animals, including the processes of absorption, distribution, modification and excretion, by using scientific assessment methods in order to obtain evidence of the safety, quality and efficacy of the medicinal product, data on adverse reactions of the human body, animal to the use of a medicinal product and the effect of its interaction with other medicinal products and (or) food products, feed.

Multicenter clinical trial of a medicinal product for medical use - a clinical trial of a medicinal product for medical use, carried out by the developer of the medicinal product in two or more medical organizations under a single protocol for the clinical trial of the medicinal product.

International multicenter clinical trial of a medicinal product for medical use - a clinical trial of a medicinal product for medical use, conducted by the developer of the medicinal product in various countries under a single protocol for the clinical trial of the medicinal product.

A source: Federal Law of the Russian Federation of April 12, 2010 N 61-FZ

Clinical research- scientific research with human participation, which is carried out with the aim of assessing the efficacy and safety of a new drug or expanding the indications for the use of an already known drug. Clinical trials can also investigate the efficacy and safety of new invasive (including surgical) and non-invasive treatments and diagnostics.

Clinical researches all over the world are an integral stage in the development of drugs, which precedes its registration and widespread medical use. In clinical trials, a new drug is being studied to obtain data on its effectiveness and safety. Based on these data, the authorized health authority makes a decision on the registration of the drug or refusal of registration. A drug that has not passed clinical trials cannot be registered and put on the market.

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    Clinical studies are called “... any study involving human subjects, with the aim of identifying or verifying the clinical, pharmacological and / or pharmacodynamic properties of one or more investigational medical products, and / or adverse reactions to one or more medical products and / or studies of absorption, distribution, metabolism and excretion of one or more medical products in order to confirm its (their) safety and / or effectiveness. " (EU Directive)

    Requirements for planning and conducting clinical trials (CTs) are formulated in the GoodClinicalPractice (GCP) standards. Compliance with the GCP rules ensures the accuracy of the data received and the observance of patients' rights. These rules apply to all CTs, whether conducted by a pharmaceutical company or research physicians as part of their dissertation research, new drugs, new treatments, new medical technology, or medical devices, including dental materials.

    Clinical trials are carried out in 4 phases (Figure 9.2).

    Rice. 9.2. The scheme for creating a new drug and the phase of the 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 (on average 10-20 adult males). The main goals of this phase are to determine the highest tolerated dose, identify adverse events, study pharmacodynamics and pharmacokinetics, and resolve the question of the meaning of continuing further work on a new drug.

    In Phase II clinical trials the first controlled (see below) studies of drugs are being carried out in a small number (100-300) of patients with a disease for the treatment of which they are planned to be used. The main goals of phase II are to confirm the therapeutic effect, select an effective dose and dosage regimen, and further assess the tolerability of the new drug.

    PhasesIII clinical trials are multicenter controlled trials involving large (and, where possible, diverse) patient populations. Usually 1000-3000 patients take part in this stage. The main goals of the III phase of CT 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 frequent undesirable effects and possible interactions with other drugs.

    After the successful completion of phase III, the manufacturer 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 the Expertise of Medicinal Products, the Pharmacological and Pharmacopoeial Committees.

    Figure 9.3. Registration scheme for a new drug in Russia

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

    Any drug can be prescribed only for registered indications. In the case when, in the process of using a drug or during scientific research, proposals arise for a new indication for its use, additional tests are required, starting from phase II, to register this indication.

    Clinical trials

    Clinical research- scientific research of the efficacy, safety and tolerability of medical products (including medicines) in humans. The standard for good clinical practice indicates that the term is fully synonymous with this term. clinical trial, which, however, is less preferable due to ethical considerations.

    In healthcare clinical trials conducted in order to collect safety and efficacy data for new drugs or devices. Such trials are carried out only after satisfactory information on the quality of the product, on its preclinical safety, has been collected, and the relevant health authority / Ethics Committee of the country where the clinical trial is being carried out has given permission.

    Depending on the type of product and its stage of development, researchers enroll healthy volunteers and / or patients initially in small pilot, “sighting” studies, followed by larger patient studies, often comparing this new product to prescribed treatments. As positive safety and efficacy data are collected, the number of patients typically increases. Clinical trials can range in size from a single center in one country to multicenter trials covering centers in many countries.

    The need for clinical trials

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

    Authorized control bodies

    In most countries of the world, ministries of health have special departments responsible for checking the results of clinical trials carried out on new drugs and issuing approvals for the supply of a medical product (drug, apparatus) to a network of pharmacies.

    IN THE USA

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

    In Russia

    In Russia, the Federal Service for Surveillance in Healthcare and Social Development (Roszdravnadzor of the Russian Federation) oversees clinical trials conducted in Russia.

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

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

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

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

    Control practice in other countries

    Similar institutions exist in other countries.

    International requirements

    The basis for conducting clinical trials (trials) is the document of the international organization "International Conference on Harmonization" (ICH). This document is called the Guideline for Good Clinical Practice (GCP Standard Description; Good Clinical Practice translates to Good Clinical Practice).

    Typically, in addition to physicians, there are other clinical research specialists working in the clinical research field.

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

    Clinical research should be scientifically based, detailed and clearly described in the research protocol. Assessment of the risk-benefit ratio, as well as review and approval of the study protocol and other documentation related to the conduct of clinical trials, are the responsibility of the Organization's Expert Council / Independent Ethics Committee (IRB / IEC). After obtaining approval from the ESP / IEC, the clinical trial can begin.

    Types of clinical trials

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

    Randomized a clinical trial in which patients are randomly assigned to treatment groups (randomization procedure) and have the same opportunity to receive the investigational or control drug (comparator or placebo). In a nonrandomized study, the randomization procedure is not performed.

    Controlled(sometimes used as a synonym "comparative") a clinical trial in which an investigational drug, the efficacy and safety of which has not yet been fully studied, is compared with a drug whose efficacy and safety are well known (comparator drug). This can be a placebo (placebo-controlled trial), standard therapy, or no treatment at all. In an uncontrolled (noncomparative) study, a control / comparison group (a group of subjects taking a comparison drug) is not used. In a broader sense, controlled research means any research in which potential sources of bias are controlled (if possible, minimized or eliminated) (that is, it is conducted in strict accordance with the protocol, monitored, etc.).

    When conducting parallel study subjects in different groups receive either only the study drug or only the comparison drug / placebo. V cross In studies, each patient receives both drugs being compared, as a rule, in a random sequence.

    Research can be open when all study participants know which drug the patient is receiving, and blind(disguised) when one (single-blind study) or multiple parties to a study (double-blind, triple-blind, or full-blind study) are kept in the dark about the distribution of patients by treatment group.

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

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

    V parallel A study compares two or more groups of subjects, one or more of whom are receiving the study drug and one group of which is the control group. Some parallel studies compare different treatments without including a control group. (This design is called independent group design.)

    Cohort A study is an observational study in which a selected group of people (cohort) is observed over a period of time. The outcomes of subjects in different subgroups of a given cohort, those who have or have not (or have undergone to varying degrees) treatment with the study drug are compared. V prospective cohort study cohorts are composed in the present and observed in the future. In a retrospective (or historical) cohort study, cohorts are matched from archival records and their outcomes are traced from then to the present. Cohort trials are not used to test drugs, but rather to determine the risk of contributing factors that cannot be controlled or ethically controlled (smoking, being overweight, etc.).

    In research case-control(synonym: study of similar cases) comparing people with a particular disease or outcomes ("case") with people in the same population who do not have the disease or who did not have the given outcome ("control"), in order to identify the relationship between the outcome and prior exposure to certain risks; factors. In a case series study, multiple individuals are observed, usually receiving the same treatment, without using a control group. In the description of the case (synonyms: case from practice, history of the disease, description of a single case), a study of treatment and outcome in one person is conducted.

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

    When testing a medicinal product or method, experimenters usually do not have sufficient time and ability to reliably establish whether the method under test produces a sufficient effect, therefore, statistical methods are used in a limited clinical trial. Many diseases are very difficult to cure and doctors have to fight for every step towards recovery. Therefore, the test monitors the many symptoms of the disease and how they change when exposed.

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

    To cut off these and other lubricating effects of the therapeutic method of effects, the following techniques are used:

    • research is done placebo controlled... That is, patients are divided into two groups, one - the main one - receives the study drug, and the other, the control group, is given a placebo - a dummy.
    • research is done blind(eng. single blind). That is, patients do not realize that some of them are receiving a placebo, not an investigational new drug. As a result, patients in the placebo group also think they are getting treatment, when in fact they are receiving a dummy. Therefore, the positive dynamics from the placebo effect took place in both groups and dropped out when compared.

    V double blind In the (double blind) study, not only the patients, but also the doctors and nurses who give the drugs to the patients, and even the clinic's management, themselves do not know what they are giving them - whether it is really the study drug or a placebo. This eliminates the positive impact of confidence on the part of doctors, clinic management and nursing staff.

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