1. The head of a medical organization that conducts a clinical trial of a medicinal product for medical use appoints a researcher responsible for conducting such a study and having a medical specialty corresponding to the clinical trial of the medicinal product, with at least three years of experience in clinical drug research programs. and, at his suggestion, appoints co-investigators from among the doctors of this medical organization.

2. The researcher selects patients who, for medical reasons, can be recruited to participate in a clinical trial of a medicinal product for medical use.

3. The researcher and co-investigators must be familiar with the results of the preclinical study of the medicinal product contained in the investigator’s brochure, the draft protocol for the clinical trial of the medicinal product for medical use, developed by the developer of the medicinal product or other legal entity involved in organizing the clinical trial of the medicinal product for medical use. , and other materials of such research.

3.1. The head of a medical organization, within a period not exceeding three working days from the date of the start of a clinical trial of a medicinal product for medical use, reports this to the authorized federal executive body that issued permission to conduct such a trial, in the form established by it.

4. Organizations organizing a clinical trial of a medicinal product for medical use and specified in Part 3 of Article 38 of this Federal Law, if it is necessary to make changes to the protocol for a clinical trial of a medicinal product for medical use, report this to the authorized federal executive body that issued the permission to conduct such research, in the form established by him.

(see text in the previous edition)

4.1. The notification form for changes to the clinical trial protocol for a medicinal product for medical use must contain the following information:

1) name, identification number and date of the clinical trial protocol;

2) date of amendments to the clinical trial protocol;

3) name and location of the applicant;

4) the name of the organization involved by the developer of the medicinal product in organizing the clinical trial (if any);

5) names and locations of medical organizations in which the clinical trial is being conducted;

6) the date of issue of permission to conduct a clinical trial and the number of this permission;

7) changes made to the clinical trial protocol.

5. Within a period not exceeding thirty working days from the date of receipt of the message specified in Part 4 of this article, the authorized federal executive body considers this message in the manner established by it and decides to amend the clinical trial protocol of a medicinal product for medical use or to refusal to make such changes. When considering a message about the need to make changes to the clinical trial protocol of a medicinal product for medical use in order to assess the validity of the proposed changes and determine the degree of risk for patients participating in clinical trials, the authorized federal executive body may involve ethics council experts.

(see text in the previous edition)

6. A clinical trial of a medicinal product for medical use may be suspended or terminated if a danger to the life or health of patients is discovered during its implementation. In the event of a danger to the life or health of a patient participating in a clinical trial of a medicinal product for medical use, researchers are obliged to inform the head of the medical organization and the organization that has received permission from the authorized federal executive body to organize a clinical trial of the medicinal product. The decision to suspend a clinical trial of a medicinal product for medical use is made by the head of a medical organization and (or) an organization that has received permission from the authorized federal executive body to organize a clinical trial of a medicinal product for medical use; the decision to terminate such a study is made by the authorized federal executive body on based on a written message from the head of a medical organization or an organization that has received permission from the authorized federal executive body to organize a clinical trial of a medicinal product for medical use.

7. Within a period not exceeding five working days from the date of completion, suspension or termination of a clinical trial of a medicinal product for medical use, a notification about this is sent by the organizations specified in Part 3 of Article 38 of this Federal Law to the authorized federal executive body as established by it form .

8. The form for reporting the completion, suspension or termination of a clinical trial of a medicinal product for medical use must contain:

1) information about the medical organization or medical organizations that conducted this study;

2) description of this study;

3) data of the researcher (last name, first name, patronymic, place of work, position held, specialty, work experience in clinical drug research programs, list of clinical drug trials in which he took part (periods of participation) as a researcher or co-investigator);

(see text in the previous edition)

4) the result of this study (completion, suspension or termination of this study, indicating their reasons and impact on the assessment of its results, the overall assessment of the risk and expected benefit from the use of the investigational medicinal product, as well as expected further actions).

8.1. If the federal executive body exercising the functions of control and supervision in the field of healthcare identifies violations of the rules of good clinical practice during a clinical trial of a medicinal product that affect the completeness and (or) reliability of this clinical trial, the specified federal executive body shall suspend the conduct of this clinical trial. research and issues an order to the medical organization in which this clinical trial is being conducted to eliminate the identified violations. If the medical organization fails to eliminate the identified violations within the time period established in the prescription, the specified federal executive body makes a decision to terminate the clinical trial of the medicinal product and sends it to the federal executive body responsible for the development and implementation of state policy and legal regulation in the field of healthcare, a conclusion on the identification of violations of the rules of good clinical practice during the conduct of this clinical trial in order to make a decision to cancel the permission to organize this clinical trial from the date of the decision to suspend the clinical trial of the medicinal product.

(see text in the previous edition)

9. The authorized federal executive body publishes and places on its official website on the Internet a message about the completion, suspension or termination of a clinical trial of a medicinal product for medical use within a period not exceeding five working days from the date of its receipt, in the manner established by it .

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

Concept of clinical trials

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 carried out to obtain evidence of the effectiveness of drugs.

But animals are different from humans, so the way experimental mice react to a drug does not at all mean that people will get the same reaction.

If we define what clinical research is, we can say that it is a system of using various methods to determine the safety and effectiveness of a drug for humans. During the study of 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 decision 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, this person is the pharmaceutical company that developed the drug.

All results of clinical trials and their progress must 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 the registration of a drug and its mass release for medical use. Those drugs that have not passed the study cannot be registered and put on the drug market.

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

Goals of laboratory research

Conducting research on any drug has several goals:

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

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

Classification of studies

Such an issue as the classification of drug studies can be approached from different angles. Depending on the factor, the types of studies may be different. Here are some classification methods:

1. According to the degree of intervention in the patient’s management tactics.
2. Studies may differ in their objectives.

In addition, there are also types of laboratory tests. Let's look at this question in more detail.

Types of intervention studies in patient treatment

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

1. Observational. During such a study, no intervention occurs; information is collected and the natural course of all processes is observed.
2. Non-interventional or non-interventional study. In this case, the drug is prescribed according to the usual regimen. The study protocol does not decide in advance the issue of assigning a patient to any treatment tactics. The prescription of the drug is clearly separated from the patient's inclusion in the study. The patient does not undergo any diagnostic procedures; the data is analyzed using epidemiological methods.
3. Intervention study. It is carried out when it is necessary to study yet unregistered drugs or to find out new directions in the use of known drugs.

Classification criterion - purpose of the study

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 from or to prevent relapse. This is usually how vaccines and vitamin preparations are studied.
• Screening studies allow us 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 studies provide an opportunity to study the effectiveness and safety of drugs and treatment methods.

• Quality of life studies are conducted to understand how the quality of life of patients with certain diseases can be improved.
• Expanded access programs involve the use of an experimental drug in patients with life-threatening diseases. Typically such drugs cannot be included in laboratory tests.

Types of research

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

• A pilot study is conducted to collect the necessary data for the next stages of studying the drug.
• Randomization involves assigning patients randomly to groups, they have the opportunity to receive both the study drug and the control drug.

• A controlled drug study examines a drug whose effectiveness and safety are not yet fully known. It is compared to an already well-studied and well-known drug.
• An uncontrolled study does not imply a control group of patients.
• A parallel study is carried out in several groups of patients who receive the drug being studied.
• In crossover studies, each patient receives both drugs, which are compared.
• If the study is open, then all participants know the drug that the patient is taking.
• A blinded or masked study involves two parties who are unaware of the patients' group assignment.
• A prospective study is conducted with patients assigned to either receive or not receive the study drug before the outcome occurs.
• When retrospective, the results of studies already conducted are considered.
• There may be one or more clinical research centers involved, depending on which there are single-center or multi-center studies.
• In a parallel study, the results of several groups of subjects are compared, among which one is a control, and two or more others receive the study drug.
• A case study involves comparing patients with a particular disease with those who do not, in order to determine the relationship between the outcome and previous exposure to certain factors.

Research stages

After the production of a drug, it must undergo all studies, and they begin with preclinical ones. Conducted on animals, they help the pharmaceutical company understand whether the drug is worth exploring further.

A drug will only be tested in humans once it has been proven that it can be used to treat a particular condition and is not dangerous.

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

Phase one

Clinical research of the drug at the first stage is limited to recruiting volunteers from 20 to 100 people. If a drug is being studied that is too toxic, 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 is the drug tolerated by humans?
• Pharmacological properties.
• The period of absorption and excretion from the body.
• Preliminarily assess the safety of its use.

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 given a certain dose of the drug; if it is well tolerated, then the dosage is increased for the next group. This is done until the intended safety levels are achieved or side effects begin to appear.
2. Repeated ascending dose studies. A group of volunteers receives a small dose of the drug many times, after each dose, 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 until a certain level.

Second phase of research

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

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

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

Phase 3 research

After the first two phases, drugs continue to be studied in the third phase. A large group of people up to 3000 people participates. 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 medicine has confirmed its safety and effectiveness at this stage, a registration dossier is prepared. It contains information about the results of the study, the composition of the medicine, expiration date and storage conditions.

Phase 4

This stage is already called post-registration research. The main objective 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 drugs, what is the most optimal duration of therapy, and how the drug affects patients of different ages is also being studied.

Study protocol

Any research protocol must contain the following information:

• The purpose of studying the medicine.
• The tasks that researchers set for themselves.
• Study design.
• Study methods.
• Statistical issues.
• Organization of the research itself.

Protocol development begins before all studies begin. Sometimes this procedure can take several years.

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

Recently, various methods of clinical laboratory research have been increasingly used. 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 patient therapy based on proven scientific data, and it is impossible to obtain them without conducting a comprehensive study.

Today we will get acquainted with a profession that many of us never thought about. We are all used to buying at the pharmacy in full confidence that they will help and not harm. But who is responsible for the safety of pharmacological drugs?

Healthcare managers, pharmacologists, scientists, medical equipment suppliers, nurses and paramedics, insurance experts and psychologists: tens of thousands of professionals are responsible for the smooth functioning of the healthcare industry! You can delve into the intricacies of everyone’s work and see the interesting features of medical specialties only from the inside, finding yourself in places where patients are usually not allowed to look.

Before going on sale, each drug goes a long way - from testing on animals in laboratory conditions to testing on real patients in hospitals. And on this path, each drug accompanies clinical research specialist.

Our expert: Lev Korolkov, St. Petersburg, clinical research specialist at OCT.

About a profession with a strange name

My position in Russia sounds like a clinical research specialist, but this is official, in short - a monitor. The foreign name is clinical research associate or simply CRA.

In general, after graduating from the St. Petersburg State Chemical-Pharmaceutical Academy, I had little idea in which area of ​​pharmaceutics I would work. One day, a classmate of mine, who was already working as a monitor, told me how she travels to different cities and conducts some research there. After learning more about the nature of the work, I decided that this was a good option. Since then, clinical research has been my profession.

About drug testing

In fact, people started thinking about the safety of medicines relatively recently. Serious development of clinical trials of new drugs began after the largest pharmacological tragedies of the 20th century: sulfonamide and thalidomide.

The first happened in 1937, when the pharmaceutical company M. E. Massengill released a liquid form of a sulfonamide drug for children - before the invention of antibiotics, this group of drugs was the most effective in the fight against infectious diseases. However, the solvent used for the new mixture turned out to be terribly poisonous. Soon after the drug was launched on the market, it became known that 8 children and 1 adult patient died after taking it. Pharmacists sounded the alarm and began a campaign to recall the drug from pharmacies, but before the end of the investigation, the deadly mixture managed to claim the lives of 107 people.

The thalidomide tragedy occurred 20 years later, when uncontrolled use of thalidomide, a drug recommended for pregnant women as a sedative, led to the birth of more than 10 thousand children with severe developmental defects.

By the way, just recently, Americans paid their final respects to a legendary employee of the US Food and Drug Administration named Frances Oldham Kelsey, whose courage prevented a tragedy on the other side of the Atlantic (even before the first cases of congenital deformities, the woman suspected something was wrong with thalidomide and refused to register it for sale in the United States).

Since then, it has become clear that every new drug needs to be tested for safety and effectiveness, and to ensure that its trials are ethical and do not harm the volunteers and patients who agree to try the new drug.

About romance and flights

Travel does take up a significant portion of a clinical research scientist's job. The fact is that in order to obtain objective statistical data, it is almost impossible to find the required number of suitable patients in one city. Therefore, we need many hospitals - in different cities, and representatives of my specialty travel a lot, and by air: otherwise we would lose too much time on the road.

In addition, in one hospital, the same doctors-researchers will care for patients, one laboratory, one CT machine will be used. An error in dosing, measuring a tumor or potassium in the blood (not to mention falsifying data) will lead to systematic inaccuracy of all data. This will put an end to the entire clinical trial. But if this happens in only one hospital out of many participating in the study, then the data may still be reliable.

At first, trips to different cities seemed like real romance to me. But over time, having flown hundreds of thousands of kilometers, I got used to it, and it became a normal routine. Like George Clooney’s character in the movie “Up in the Air,” I literally became a professional airline passenger: I immediately find the fastest line at pre-flight security, pack a suitcase in 10 minutes, in which everything has its place, and I know the airport layouts like my own. five fingers.

As a rule, each of my business trips lasts 1-2 days. The night before I fly from St. Petersburg to another city - Krasnoyarsk, Kazan, Barnaul, Rostov-on-Don... In the morning I wake up in the hotel and go to the medical facility where our drug is being tested. There I communicate with doctors and check all the documents indicating that patients agree to take part in testing the drug. After lunch, I check the hospital’s drug supplies, laboratory samples and all the materials needed for the study. In the evening I go to the airport again, and from there back to St. Petersburg.

I work regularly on the road, it’s already the norm: sit in a waiting room/taxi/plane and write another report or letters to the project manager. I can’t say that this is a comfortable lifestyle, because night flights (“zombie flights,” as I call them) or flights after a working day do not allow you to properly rest or just get enough sleep, but even you get used to it. If I have free time after work and I’m in another city, I try to take a walk in unfamiliar places or go to the gym at the hotel.

Often my friends think that such a schedule is crazy. Here, perhaps, not everything is so simple. I wouldn’t say that this job is critically different from many others in terms of workload. Everything very much depends on the current situation and the availability of projects. When a project is in full swing and deadlines are pressing, then, of course, you have to work on the plane, in a taxi, and at home on the weekends, but this is rather a temporary phenomenon. At least in our company. In investment banking, for example, they work much more, as far as I know. Personally, I am quite able to combine my personal life with work. Of my 15 fellow monitors, seven are married. Our team is friendly: when our schedule allows, we regularly get together in pubs.

Representatives of my profession need a balance between following instructions and psychological skills. The first is taught in trainings, and you can’t do without it. And you study psychology mostly on your own: you look for an approach to different researchers, smooth out conflicts, and set doctors up for active work.

About patients who are ready for anything

I will say a few words about the document called “Informed Consent”. One should not think that checking the fact that the patient consciously agreed to take part in a drug trial is an empty formality. Signing the consent and correctly reflecting this process in the patient’s chart is the cornerstone of the monitor’s visit, the verification of which allows us to understand a lot about the observance of the patient’s rights.

How is it that a person voluntarily agrees to try a new medicine on himself? First, patients never pay anything to participate in a clinical trial. But volunteers can be paid, especially when the safety of the drug is being tested (as a rule, healthy people are involved for this).

In addition to free treatment, participants also receive a thorough free examination. By the way, it is not uncommon for patients to be treated with similar but approved drugs outside of the study. But not all of these drugs are affordable for them.

In other cases, patients agree to a trial because they have already tried all existing treatments and nothing has helped them. They simply have no other options but to try new drugs that are still being studied. This is especially true for cancer patients.

About placebo and nocebo

A placebo drug (Latin placere - “I will like it”) does not work due to a real effect, but simply because it is positively perceived by the patient and has a psychological effect on him. There is also the opposite phenomenon - nocebo (“I’ll do harm”) - when, due to the subjective perception of the drug, a deterioration occurs.

There is also such an interesting term as randomization - the process of randomly assigning study subjects to treatment or control groups, allowing to minimize subjectivity. The process is needed so that it is not the doctor who decides who will be treated with what (there is a possibility that “mild” patients will be given a placebo, and “severe” patients will be given the study drug), but rather the case.

The blind method of the study is that the patient does not know which drug he will take: study/placebo/comparison drug. A double-blind method is the same thing, but when the experimenter (and the monitor, and often the statistician) also does not know what the patient is taking. Both are necessary to reduce subjective factors (“placebo effect”) that can affect the results of the study.

Everything is clear with the patient: if he knows that he is taking the study drug, then he has high expectations from the treatment. This may affect the subjective assessment. But the doctor also gives a subjective assessment of the patient’s current condition, which, in turn, can also be influenced by information about the drug.

There are also so-called vulnerable research subjects. These include medical students, clinic staff, military personnel and prisoners, as well as terminally ill people, homeless people, refugees, minors, and also persons unable to give consent. If these categories participate in the study, we always ensure that they are not pressured by management.

Situations where a drug (real or placebo) does not work, and the patient experiences severe adverse events, are always prescribed in the clinical trial protocol. If a person's condition worsens or he simply decides to abandon the experiment, he will not be forced to undergo treatment. In this case, the patient is provided with medical assistance if necessary or referred to other specialists.

About self-realization

It may seem to some that the work of a clinical research specialist is a rather boring clerical task that does not require any special knowledge and skills. But this is not so: I always feel responsible, because my punctuality and attentiveness determine how fully the possible side effects associated with taking the drug will be reflected, and, no less important, whether the rights of patients will be respected. After all, every day thousands of people voluntarily agree to test a medicine on themselves, which, perhaps, in a few years, will make it possible to treat a particular disease faster and more reliably.

Are the new drugs really that effective? I don’t presume to judge - I’m just a small part of a large system that accompanies medicine from the test tube to the pharmacy counter. But personally, the effect of treatment with modern drugs is always positive. I attribute this to the fact that I do not buy medications at random, but only after consulting a doctor and proper diagnosis.

Olga Kashubina

Photo thinkstockphotos.com

In March 2017, the LABMGMU company passed an international audit. Its activities were audited by the well-known transnational company FormaliS, which specializes in audits of pharmaceutical companies, as well as companies that conduct preclinical and clinical studies.
FormaliS is trusted by the largest pharmaceutical companies in Europe, Asia, North and Latin America. The FormaliS certificate is a kind of quality mark that provides a company that has passed its audit with a good reputation in the international pharmaceutical community.
Today in the LABMGMU studio the president of FormaliS Jean-Paul Eycken.

Dear Jean-Paul, please tell us about your company. When was it created? What are her competencies and priorities?

FormaliS was founded in 2001, that is, more than 15 years ago. Our management is located in Luxembourg. But FormaliS has offices all over the world - in the USA, Brazil, Thailand, and European countries.
The activities of our company are aimed at controlling the quality of drugs that enter the pharmaceutical market. We do not interfere in production, but are exclusively engaged in quality control - we conduct audits of pharmaceutical companies and trainings.

- Are you invited for inspections by pharmaceutical companies from all over the world?

Yes. But, as you know, 90 percent of the pharmaceutical business is concentrated in Japan, the USA, and also in European countries. Large transnational pharmaceutical companies with which FormaliS works can conduct international studies in any country - for example, in Poland, Canada, Russia, the USA. So I went on audits to different countries around the world.

- How long have you been cooperating with Russian pharmaceutical companies?

The contract research organization LABMGMU became the first Russian company to invite me for an audit.
I have been to Russia several times - to Moscow, St. Petersburg, Rostov. Conducted audits for American and Western European sponsoring companies conducting international multicenter clinical trials, including in Russian medical institutions. My audits ensured the sponsor's confidence in the full compliance of the studies conducted with the legislation and international rules of GCP, GMP and GLP.

Do contract research organizations often order audits?

Infrequently. Contract research organizations ordering international audits - no more than 15 percent. In most cases, FormaliS deals with pharmaceutical, biotechnology, medical device and food supplement companies that develop and register new products. There are 85 percent of them. The focus of the audit depends on the wishes of the client. They know their product and want to bring it to the global pharmaceutical market. They want to be sure that the research on their product is reliable and of high quality. A company like Formalis is hired to audit the contract research organization.
LABMGMU, as I already said, is generally the first Russian organization with which I entered into an audit contract. And the fact that LABMGMU ordered such an audit indicates the high competence of its management and provides good prospects. Conducting an international audit lays a solid foundation, a reliable basis for the development of any contract research organization.

- What do auditors pay special attention to when conducting an audit?

Both the FormaliS Company's customers and we, the auditors, do one thing in common - we release new drugs onto the pharmaceutical market. And the health of patients depends on the quality of the medicines to which we give a start in life. Every auditor should know this. If he sees a danger for volunteers, for patients. Not just those participating in clinical trials. I'm talking about people who will be treated with new drugs in the future. Before releasing a medicine to the market, we must do everything to ensure its effectiveness and safety, and the reliability of the preclinical and clinical studies conducted. Therefore, compliance with the rules and laws governing the circulation of medicines is so important.
When I audit a contract research organization, clinical site or laboratory, I look not only at the level of professional knowledge, training and experience of the employees of the company I am auditing, but also at their motivation. Motivation and empathy are very important. Motivation is to do a good job. A system of work in accordance with international standards is needed. If you have motivated staff, you can achieve excellent results.

- What meaning do you put into this word in this case?

In the pharmaceutical business, motivation is the desire, when creating and registering a drug, to carefully conduct all studies according to all the rules, not to neglect any detail in order to ensure the effectiveness and safety of the new drug. In the pharmaceutical business, conscientious work according to the rules is the key to patient safety.
- Is there any difference between the audit that you conduct at the request of sponsors and the audit that you conduct at the request of a contract research organization?
- All audits are different from each other because each audit is unique. No two are alike, because there are no templates in our business. This depends on the type of organization being audited. This could be a contract research organization, a medical institution, or a laboratory. Every situation is non-standard. For example, a contract research organization in the USA and in Russia: different regulatory requirements, different language, different people.

Jean-Paul, in your opinion, what should sponsors pay special attention to when choosing a contract research organization to conduct clinical trials?

First of all, you need to look at the motivation of the company’s employees and the level of their professional training. How they comply with legislation and good practice. It is also important that the company has the opportunity to collect data from studies conducted in different countries into a single database for generalization and analysis. And this information must be available in all countries in which the drug being prepared to enter the market is circulated. A medicine that has not undergone sufficient testing should not enter the pharmaceutical market.
This is important because the health of millions of people depends on the quality of the medicine that reaches the pharmaceutical market.

- Thank you very much, Jean-Paul, for taking the time for this interview.

I was very pleased to work with the employees of the LABMGMU company. They are true professionals and I thoroughly enjoyed communicating with them.

Clinical drug trials (GCP). GCP Stages

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

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

Clinical trials of a drug are a necessary stage in the development of any new drug, or the expansion of indications for the use of a drug already known to doctors. At the initial stages of drug development, chemical, physical, biological, microbiological, pharmacological, toxicological and other studies are carried out on tissues (in vitro) or on laboratory animals. These are so-called preclinical studies, the purpose of which is to obtain scientific estimates and evidence of the effectiveness and safety of drugs. However, these studies cannot provide reliable information about how the drugs being studied will act in humans, since the organism of laboratory animals differs from humans both in pharmacokinetic characteristics and in the response of organs and systems to drugs. Therefore, clinical trials of drugs in humans are necessary.

A clinical study (test) of a medicinal product is a systemic study of a medicinal product through its use in humans (patient or healthy volunteer) in order to assess its safety and effectiveness, as well as to identify or confirm its clinical, pharmacological, pharmacodynamic properties, assess absorption, distribution, metabolism, excretion and interaction with other drugs. The decision to initiate a clinical trial is made by the customer, who is responsible for organizing, monitoring and financing the trial. Responsibility for the practical conduct of the research rests with the researcher. As a rule, the sponsor is a pharmaceutical company that develops drugs, but a researcher can also act as a sponsor if the study was initiated on his initiative and he bears full responsibility for its conduct.

Clinical trials must be conducted in accordance with the fundamental ethical principles of the Declaration of Helsinki, GСP (Good Clinical Practice) and applicable regulatory requirements. Before the start of a clinical trial, an assessment must be made of the relationship between the foreseeable risk and the expected benefit for the subject and society. The principle of priority of the rights, safety and health of the subject over the interests of science and society is put at the forefront. The subject can be included in the study only on the basis of voluntary informed consent (IS), obtained after a detailed review of the study materials. Patients (volunteers) participating in testing a new drug must receive information about the essence and possible consequences of the tests, the expected effectiveness of the drug, the degree of risk, enter into a life and health insurance agreement in the manner prescribed by law, and during the tests be under constant supervision of qualified personnel. In the event of a threat to the health or life of the patient, as well as at the request of the patient or his legal representative, the head of the clinical trial is obliged to suspend the trial. In addition, clinical trials are suspended if a drug is unavailable or insufficiently effective, or if ethical standards are violated.

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

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

Phase I. First experience of using a new active substance in humans. Most often, studies begin with volunteers (healthy adult men). The main goal of the research is to decide whether to continue working on a new drug and, if possible, to establish the doses that will be used in patients during phase II clinical trials. During this phase, researchers obtain preliminary data on the safety of the new drug and describe its pharmacokinetics and pharmacodynamics in humans for the first time. Sometimes it is impossible to conduct phase I studies in healthy volunteers due to the toxicity of this drug (treatment of cancer, AIDS). In this case, non-therapeutic studies are carried out with the participation of patients with this pathology in specialized institutions.

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

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

• - more effective than known drugs of similar action;
• - has better tolerability than known drugs (with the same effectiveness);
• - effective in cases where treatment with known drugs is unsuccessful;
• - more economically beneficial, has a simpler treatment method or a more convenient dosage form;
• - in combination therapy, it increases the effectiveness of existing drugs without increasing their toxicity.

Phase IV. Studies are conducted after the drug is marketed in order to obtain more detailed information about long-term use in various patient groups and with various risk factors, etc. and thus more fully evaluate the drug strategy. The study involves a large number of patients, which makes it possible to identify previously unknown and rare adverse events.

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

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

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

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

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

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

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