Hypotheses, research methods and its design. Retrospectively estimated possible causes or risk factors, but this is not historical control. Appointment of angioprotectors, resorption drugs

• Evidence Medicine

• Design Medical Research

• Pivina L.M, Ph.D., Assistant

• departments of internal diseases number 2

Previous events

• Reducing infant mortality and rapid growth of the population

• Changes in the structure of morbidity with acute diseases to the predominance of chronic

• Changes in the etiological nature of diseases - from infectious agents on behavioral factors

• Stormy development of medical science and growth of medical technology

• Development of social insurance systems

What does evidence-based medicine mean?

• "... conscientious, accurate and meaningful use of the best results of clinical research for making decisions in assisting a specific patient."

• (Sackett D., Richardson W., Rosenberg W., Haynes R. Evidence-Based Medicine. How to Practice and Teach EBM. Churchill Livingstone, 1997.)

Concept of evidence medicine

• The purpose of the concept of evidence-based medicine is to give doctors the opportunity to find and use, when taking clinical decisions, scientifically based facts obtained during the correct clinical studies have increased the accuracy of the projection of the outcomes of medical interventions.

• The concept is based on two basic ideas:

• Each clinical solution of the doctor should be taken into account with scientific data.

• The weight of each fact is the greater, the stronger the scientific research method, during which it was obtained.

• Finger MA 2006

When did evidence-based medicine appear?

• 1940 g - the first randomized studies (use of streptomycin with tuberculosis)

• 1960 - tragedy associated with talidomide

• 1962 US Committee for Medications Control and Food Products introduced rules requiring controlled research of new drugs

• 1971 - Kokran raised the question of insufficient scientific evidence

• 1980-90 - drawing attention to the need to include systematic reviews in clinical guidelines

• 1994 - First Cochrane Colloquium in Oxford

• 1994 - EBM term

• 1996 - Most British doctors already know the term EBM

• 1996 - British Health Minister stated that his main task is to promote the concept of EBM

• 1996 - EBM term in leading British newspapers

• 1999 - BMJ issues EBM reference (edition in USA ½ million)

• 2001 - German, Spanish, Russian, Japanese edition

• DM was named after Archie Cochrane Archie (Archie Cochrane) of the English epidemiologist, indicating the need to evaluate with the help of controlled clinical research on the role of specific clinical intervention and storing results in a special database on the effectiveness of medical care.

• For the first time, they were formulated by the concept of evidence-based medicine.

• The studies show that

• for 2/3 patients doctors

• need information but

• get it only in

• A small number of cases. Where to get the necessary information?

• Observations show that in some domestic magazines up to ½ articles are advertising in content, design, or related to printed advertising

To keep up with the times .......

• "... the doctor needs to read 10 magazines, approximately 70 original abstract articles per month ..."

• Sackett D.L. (1985)

• "... You need to read 15 articles of 365 days a year ..."

• McCrory D.c. (2002)

• The time for reading a practitioner for reading is less than 1 hour per week

The relationship of the practitioner and medical information

• Information boom

• Difficulties in finding reliable ("evidence") information

• Difficulties in the analysis of information

• Difficulties in making effective clinical decisions

• Medical errors

• Purpose of unreasonable interventions

Justification of the need to regulate

• In the US, 98,000 deaths since a year from medical errors (IOM, 2000)

• Only 30% of medical interventions with reliably proven effectiveness

• Ineffective (and sometimes harmful) interventions are widespread.

• Interventions with proven effectiveness are far from all needy

• Accessing Cocarboxylase, Riboxin, Asparkama

• Parenteral administration of vitamins as auxiliary treatment

• Appointment of angioprotectors, resorption drugs

• Preventive Purpose of Iron and Folic Acid Pregnant - Positive impact on the health of the mother and the newborn

• Mammography For early detection of breast cancer

The impact of rehabilitation training programs on the outcomes of the CBS in patients who have undergone myocardial infarction for 3 years of rehabilitation (meta-analyzes)

Components of high-quality medical care (Haynes et al'96)

Clinical epidemiology

• The basis of DM lies clinical epidemiology The section is a section of medicine using the epidemiological method for obtaining medical information based only by strictly proven scientific facts that exclude the influence of systematic and random errors.

Feelings that scientific research cause us

Framinghamheartstudy (Fremief examination ) Massachusetts, under the auspicesHeart, Lungand. Blood.

Framinghamheartstudy (Fremief examination ) A typical example of clinical epidemiology. This study began in 1948 in order to study cardiovascular health in Fremingm, staff Massachusetts, under the auspicesThe National Institute of Heart (later was renamed Vanational Institute of Heart, Lungs and Blood: Nationalheart, Lungand Blood.Institute; NHLBI). Initially, the study covered 5209 men and women. In 1971, 5124 representatives of the second generation of participants entered it - "offspring." Now researchers are planning to begin a survey of 3,500 grandchildren of those who entered the study more than 50 years ago - "Third Generation". The study does not have an equal cohort for the duration and magnitude and its value for modern medicine, and first of all cardiology, it is difficult to overestimate. Over the years of careful observation, the participants of the study revealed the main risk factors leading to diseases of the cardiovascular system: increased pressure, elevated level of cholesterol in the blood, smoking, obesity, diabetes, etc. Since the start of the study, about 1,200 articles in the main medical journals were published.

• The deviation from the norm is healthy or sick

• Diagnosis How accurate methods

• The frequency as far as this disease is found.

• Risk What factors are associated with increased risk of disease

• Forecast What are the consequences of the disease

• Treatment How will the course of the disease change in treatment?

• Prevention Does the methods of preventing the disease in healthy? Does the course of the disease improve in its early recognition and treatment?

• Cause What factors lead to the disease?

• Cost How much is the treatment of this

• diseases?

Frequency

• Frequency

• Risk

• Forecast

• Treatment

• Prevention

• Cause

Retrospective

• Retrospective (Retrospective Study) - Evaluated already past events (for example, by disease history)

• Prospective (Prospective Study) - Initially, the study plan is drawn up, the data collection and processing procedure is established, and then research is carried out on this plan.

Classification of design research

• 1. Observation studies (research - observations)

• one or more patient groups are described and observed according to certain characteristics.

• 2. Experimental studies

• the results of the intervention (drug, procedure, treatment, etc.) are estimated, one, two or more groups participate. There is a subject of research

Classification of scientific clinical studies

Structure of research

• By time:

• Cross research

• Longitudinal research

Longitudinal studies

Description of cases

• Descriptive reviews - The most "reading" scientific publications that reflect the position of the author on a specific problem

• Most often represent the history of the disease of one patient

• One of the ways to comprehend complex clinical situations

• But does not have scientific evidence

Series of clinical cases and clinical cases

Types of observational studies study of a series of cases or descriptive research

• A description of a series of cases is a study of the same intervention in individual sequentially included patients without a control group.

• For example, a vascular surgeon may describe the results of the revascularization of carotid arteries in 100 patients with brain ischemia.

Types of observational studies study of a series of cases or descriptive research, features

• describes a certain number of features of interest in the observed small groups of patients.

• relatively short period of research

• does not include any research hypotheses

• does not have control groups

• preceded by other studies

• this type of study is limited by data on individual patients.

Study Case - Control Study (Case Control Study)

• The study, the structure of which involves a comparison of two groups of participants with a developed and unknown clinical outcome (usually unfavorable) in order to identify differences in the influence of certain risk factors for the development of this clinical outcome.

• Such a study structure is most suitable when trying to determine the cause of rarely encountered diseases, for example, the development of violations by the central nervous system in children after applying a cough vaccine.

Cases:

• Cases: presence of a disease or outcome

• Control: absence of a disease or outcome

• Possible causes or risk factors are estimated, but this is not historical control.

• Answers the question "What happened?"

• Longitudinal or Longitudual Study

Studies "Case-Control"

• Design

Benefits and Disadvantages Case-Control

• Benefits

• The best design for rare diseases or conditions requiring long time intervals
• Used to test primary hypotheses
• Very short-term
• The least expensive

• disadvantages

• A large number of displacements and systematic errors
• Depends on the quality of primary descriptions and measurements
• Difficulties in the selection of the corresponding control group

• The study whose structure allows you to trace the group (cohort) participants and identify differences in the frequency of development of certain clinical outcomes.

• A group of patients is selected for a similar feature that will be traced in the future.

• Begins with the assumptions of risk or outcome factor

• Exposed to FR and not exposed

• Prospective in time, determination of the desired factors in the exhibited group

• Replies to the question "Do people get sick if they were exposed to risk factor?"

• Basically - prospective, but there are also historical cohort (retrospective)

Design

• Design

Benefits and disadvantages of cohort tests

• Benefits

• Best Design for Studying Causes, Diseases, Risk Factors and Results.
• Enough time to get strict evidence
• Many systematic errors can be avoided (occur if the outcome is known in advance)
• Allows you to estimate the relationship between the impact of risk factor and several diseases

• disadvantages

• Longitudinal
• Expensive (study of a larger number of people)
• Allows you to estimate the relationship between the disease and the effects of a relatively small number of factors (those that were identified at the beginning of the study)
• Cannot be used for rare diseases (sampling size should be greater than the number of persons with the disease studied)

Types of observation (descriptive) studies cross-study (prevalence)

• Data collected at a certain point in time.

• Types:

• Prevalence of disease or outcome
• Study of the course of the disease, stage

• Answer the question "How much?"

Results of prevalence

• Design

TERMINOLOGY

• Prevalence (Prevalence) - Prevalence. Example: Predalance IBS in a population Number of persons with IBS / Total population in percent.

• INCIDENCE (Incidence) - Primary morbidity. Example: bronchial asthma incident in children in children \u003d the number of new cases of asthma in children in children / the number of children living in families.

• Prevalance (P) is higher than the above incident (I) and a longer disease or condition

• P \u003d i x l

Randomized Controlled Test (RCI) (Controlled Clinical Trials, CCT)

• - Gold standard of any method of diagnosis and treatment.

• This is usually a study in which participants in random order (randomized) are distributed into two groups - the main (where studied intervention is used) and the control (where placebo is applied or other intervention. Such a study structure allows you to compare the effectiveness of interventions.

Scheme of typical RKK

Design

• Design

Placebo control

• Placebo control

• Active treatment

• Comparative dose characteristic

disadvantages

• disadvantages

• more often requires a long time
• Very expensive
• Not suitable for rare diseases
• Limited possibility of generalization

• Benefits

• the best data for patients
• Less offset (systematic error)
• The best to evaluate the effectiveness and verification of interventions
• If the randomized, the most strict design and reliable

Development of a research protocol

• The Protocol (Program) of the Clinical Studies is a document containing instructions for anyone who takes part in a clinical study with the specific tasks of each participant and the instructions for the implementation of these tasks.

• The protocol provides qualified conducting research, as well as the collection and analysis of data, which then come to the review of the control and permissive system.

Development of an individual registration card

• An individual registration card (ICR) is a means of collecting research data on paper conducted in the Research Center. In some studies, electronic means are also used for these purposes.

• At the first stage (1 phase) of clinical research, researchers study a new medicine or treatment method on a small group of people (20-80 people), in order to first determine its safety, set the safe dose interval and identify side effects.

• At the second stage (II phase), the studied medicine or treatment method is assigned to a greater group of people (100-300 people), to ensure whether it is effective, as well as to further verify its safety.

Stages (phases) of clinical research

At the third stage (III phase), the studied medicine or treatment method is assigned to even large groups of people (1000-3000 people) to confirm the effectiveness and safety, control of side effects, as well as to compare with frequently used drugs and methods of treatment, accumulation of information that will allow Use this medicine or treatment method is safe.

The fourth stage (IV phase) studies are carried out after the medication or treatment method was permitted for the application by the Ministry of Health of the Republic of Kazakhstan. These studies continue to test the studied drug or treatment method in order to further collect information on its impact on various groups of people and identify any side effects that manifest themselves during long-term use.

• A review, which is a serious scientific research in which the studied question is clearly formulated, the methods used to search, select, evaluate and summarize the results of various studies corresponding to the issue studied are described in detail. Systematic analysis may include meta-analysis (but its application is optional).

Meta-Analysis (Meta-Analysis)

• Summation of the results of several studies dedicated to the same topic

Basically compiled on the basis of systematized reviews. The method of statistical analysis, during which the results of several studies are combined, and the final assessment is presented in the form of one weighted indicator (and more weight is usually assigned to large research or research of higher methodological quality).

Design Medical Studies Conclusions

• RKI- maximum strength, but often expensive and time- cost

• Well prepared observation research give good results to identify causes of diseases, but not enough evidence

• Cohort studies - best for studying the flow of disease and identification of risk factors

• Research Case-Controlfast and inexpensive

Selection of research techniques

• Quantitative Research: It is designed to answer the questions: "How many" and "What quantity?" It is aimed at identifying relationships, as a rule, causal relationships between variables.

• Collection of information on the problem of the problem and mathematical analysis of the quantitative data obtained.

• The goal is to identify common patterns, characteristic not only for the surveyed group of people, but also for the entire population as a whole, which will allow the researcher to interpret the problem and make forecasts.

Qualitative research

• It is designed to answer the questions: "Who? Why? When? and where?" And aimed at a deeper study of the problem.

• The problem is considered from different points of view.

• The purpose of the study is the disclosure of the principles (patterns) on the studied population (patterns) on which the phenomena you are interested in and which will allow to give a deeper understanding of the problem.

Qualitative research

Data collection methods:

• Quantitative

• Tests and various measurement methods

• Questionnaires, questionnaires

• Formalized data collection

• Important elements are:

• The presence of the control group
• Randomization

Analysis of the data obtained

• Quantitative

• Statistics

Reliability of evidence

Design of clinical studies

Design of clinical research is a plan for its holding. The design of a specific clinical study depends on the objectives of the study. Consider three common design options:

· Clinical study in the same group (SINGLE GROUP DESIGN)

· Clinical study in parallel groups (Parallel Group Design)

· Clinical study in the Cross Model (Crossover Group Design)

Clinical study in one group

SINGLE GROUP DESIGN)

When conducting a study in one group, all subjects receive the same experimental treatment. This study model is aimed at comparing the results of treatment with the initial state. Thus, the subjects are not randomized by treatment groups.

The clinical research model in one group can be illustrated as follows:

Screening - Inclusion - Source - Treatment - Exodues

The model of one group can be used in the I phase of studies. Research models in the same group are usually not used on the III phase of clinical studies.

The main disadvantage of the research model in the same group is the absence of a comparison group. Effects of experimental treatment cannot be differentiated from the effects of other variables.

Clinical study in parallel groups

Parallel Group Design)

When carrying out clinical studies in parallel groups, the tests of two or more groups receive different therapy. To achieve statistical authenticity (to eliminate the systematic error), the subjects are distributed by groups by random distribution (randomization).

The clinical study model in parallel groups can be illustrated as follows:

Treatment A - Outcomes A

Treatment B - Exodes B

Where a, b - various drugs or various doses or placebo

Clinical studies in the design of parallel groups are expensive, long and require a large number of subjects (with a low frequency of development of events taken into account). However, clinical studies in parallel groups are the most objective in determining the effectiveness of treatment and accurate in the formulation of conclusions. Most clinical trials t. O., Are held in the design of parallel groups.

Sometimes studies in parallel groups can be used in two versions - this is a factorial and inhomogeneous model.

Factorial design - This is the design of several (more than 2) parallel groups. Such studies are conducted when it is necessary to study a combination of various drugs (or different doses of one drug).

The factorial model of a clinical study can be illustrated as follows:

Screening - Inclusion - Preparatory Period - Source - Randomization -

Treatment A - Outcomes A

Treatment B - Exodes B

Treatment C - Exodes with

Treatment in - Exodes in

Where a, b, c, d is various drugs or various doses or placebo

The factorial model is useful in assessing combined drugs.

The disadvantage of the factorial model is the need to attract a large number of subjects and as a result - an increase in research costs.

Inhomogeneous (interrupted) Model "Termination of therapy" (WithDRawal (Discontinuation) Design)

The inhomogeneous model is a variant of studies in parallel groups, where all the tests first receive experimental treatment, then to continue experimental treatment of patients with relevant reactions randomized into groups using blind research technology with double control or placebo use. This model is usually used to assess the effectiveness of experimental treatment by stopping the drug immediately after the reaction and recurrence registration or remission. In fig. 5 shows a diagram of an inhomogeneous research model.

Screening - Inclusion - Experimental treatment - Reaction to treatment - Randomization of reacted for treatment - Treatment or placebo

An inhomogeneous research model is particularly effective for evaluating drugs intended for therapy of difficult diseases. When conducting such studies, only a small percentage of subjects demonstrates reactions to treatment.

During the period of treatment, responses are identified, and the randomization phase along the inhomogeneous model is used to demonstrate that this reaction is a real, and not reaction to placebo. In addition, heterogeneous models are used to study recurrences.

The disadvantages of inhomogeneous models are:

· A large number of subjects that initially receive treatment to identify responses

· Considerable duration of the study

The preparatory period should last long enough to ensure that the patient's condition stabilized and the effect of the drug revealed more clearly. It should be noted that the percentage of subjects excluded from these studies may be high.

Ethical standards require careful consideration of the application of this research model due to the fact that when it is used, it may be necessary to exclude from therapy that the drug that brings relief to patients. Strict monitoring and clear definition of endpoint indicators are of paramount importance.

"Cross" model

CROSSOVER DESIGN)

Unlike research plans in parallel groups, "cross" models make it possible to estimate the effects such as the drugs under study and comparative courses of treatment on the same subjects. The subjects are randomized in groups in which they carry out the same coursework, but with different sequences. As a rule, there is a "wash" period between courses in order for the patients to return to the original, as well as to eliminate the undesirable effect of residual phenomena of preceding treatment on the subsequent effects. The "washing" period is optional if the analyzes of individual reactions of the subject are limited to their comparison at the end of each course, and the period of treatment lasts long enough. In some "cross-" models use preliminary "crossing", this means that patients who are excluded from research at the treatment stage can be translated into groups of alternative treatment before planned deadlines.

Screening - Preparatory Period - Condition Monitoring - Randomization - Treatment A In Group 1 and Treatment B in Group 2 - Belling Period - Treatment B in Group 1 and Treatment A in Group 2

"Cross" models are commonly used to study pharmacokinetics and pharmacodynamics, when the problem of control of variability within the population of the subjects is raised. In addition, the assumption that the first courses effects do not affect the second in pharmacokinetic and pharmacodynamic studies with a sufficient "wash" period.

"Cross" models are more economical compared to parallel group models, since in this case there is a smaller number of subjects. However, sometimes there are difficulties in the interpretation of the results. The effects of one therapy can be mixed with the effects of subsequent. It is difficult to distinguish the effects of consistent treatment from the effects of individual courses. When conducting clinical trials, the "cross" model usually requires more time than studies in parallel groups, due to the fact that each patient takes at least two periods of treatment plus "wash" period. This model also requires a greater number of features for each patient.

If the clinical conditions are relatively constant during the entire period of research, the "cross" model is effective and reliable.

The relatively low requirements for the size of the sample make "cross-" models useful in early clinical development in order to facilitate decision-making on more volumetric patterns of parallel studies. Since all subjects receive a studied drug, the "cross" studies are also effective for safety assessment.

Theoretical Validation in Sociological Research: Methodology and Methods

The very essence of the study of mixed type is research designs. After passing almost the entire path of "training materials", you are ready to get this lesson.

0 Click if it was useful \u003d k

Research design is a combination of requirements for collecting and analyzing the data required to achieve the objectives of the study. If we talk about East, then the relevant research designs are related primarily to the peculiarities of the combinatorics of elements of high-quality and quantitative approaches within a single study.
The main principles of organizing designs to the East are: 1) awareness of the theoretical direction (Theoretic DRIVE) of the research project; 2) awareness of the role of borrowed components in the research project; 3) compliance with the methodological assumptions of the basic method; 4) Work with the maximum available amount of data sets. The first principle is related to the purpose of the study (search VS confirmation), corresponding to the types of scientific reflections (induction VS deduction) and suitable in this case methods. According to the second principle, the researcher should pay attention not only to the basic strategies for collecting and analyzing data, but also additional, which could enrich the main part of the research project data, which are important and cannot be obtained using basic methods. The third principle is associated with the need to adhere to the fundamental requirements of working with data of one type or another. The essence of the latter principle is quite obvious and is related to attracting data from all available relevant sources.
Often, the East "placed" on the continuum between high-quality and quantitative studies (see Fig. 4.1). Thus, in the presented figure of the zone "A" denotes the use of exceptionally high-quality methods, the zone "B" is mainly high quality, with some quantitative components, the zone "C" is the equivalent to use of high-quality and quantitative methods (fully integrated research), zone "D" - Mostly quantitative with some high-quality components, zone "E" - exclusively quantitative methods.

Fig. Quality-mixed-quantitative continuum

If we talk about concrete designs, there are two main typology. One is suitable for the case when high-quality and quantitative methods are used at different stages of a single study, the other - for the case when an alternating or parallel qualitative and quantitative study is used as part of the research project.
The first typology includes six mixed-type designs (see Table 4.2). An example of a study in which high-quality and quantitative methods are used at different stages, is the coordination of concepts. As part of this research strategy, data collection is carried out using high-quality methods (for example, brainstorming or focus group), and the analysis is quantitative (cluster analysis and multidimensional scaling). Depending on the solid tasks (search or descriptive), it can be attributed either to the second or to the sixth design.
According to the second typology, you can allocate nine mixed type designs (see Table 3). This typology is based on two main principles. First, in the study of mixed type it is important to determine the status of each of the paradigms - whether high-quality and quantitative research have the same status or one of them is considered as the main one, and the second is subordinate. Secondly, it is important to determine how research will be conducted - in parallel or consistently. In the case of a sequential decision, it is also necessary to determine which one is the first, and which is the second in the temporary measurement. An example of a research project suitable under the framework of this typology may be a case when a qualitative study is carried out in the first phase in order to build the theory (for example, using the use of "informed theory" Anselma Strauss), and on the second - quantitative survey of a specific group of people, to the second which is applicable to the developed theory and with respect to which it is necessary to formulate a forecast for the development of the relevant social phenomenon or problem.

Table 1. Designs of mixed type studies, when using high-quality and quantitative methods within a single study *

Objectives of the study	Data collection	Data analysis
Quality goals	Qualitative data collection
	Quantitative data collection
	Qualitative data collection	Certification of quantitative analysis
	Quantitative data collection	High-quality analysis
Quantitative goals	Qualitative data collection	High-quality analysis
	Quantitative data collection	Certification of quantitative analysis
	Qualitative data collection	Certification of quantitative analysis
	Quantitative data collection	High-quality analysis

* In this table, 2-7 designs are mixed, design 1 is completely high-quality, design 8 - completely quantitative.

Table 2. Designs of mixed type studies, when using high-quality and quantitative research, as various phases of one research project *

* "Kachev" denotes a qualitative study, "quicha" - quantitative; "+" - the simultaneous conduct of the study, "\u003d\u003e" - consistent; Big letters indicate the main status of the paradigm, small - subordinate.

Of course, these typologies are not limited to all the variety of research designs, and they should be considered as possible guidelines in the planning of East.
East Designs in Estimated Research.
According to the typology of East designs, two main types can be distinguished - component and integrative. In the component design, high-quality and quantitative methods are also used in a single study, but individually from each other. In integrative design, methods belonging to various paradigms, on the contrary, are used together.
Component type includes three types of designs: triangulate, complementary and expansive. With triangulation design, the results obtained using one method are used to confirm the results obtained using other methods. In the case of complementary design, the results obtained using the basic method are specified and being finalized on the basis of the results obtained using methods that have a secondary value. When using expansive design, various methods are used to obtain information regarding various aspects of assessment, that is, each method is responsible for the specific part of the information.
Integrative type includes four types of designs: iterative, unstown, holistic and transformational. In case of iterative design, the results obtained with the help of any method are suggested or sent to the use of other methods relevant in this situation. Unstown design is associated with situations when one of the methods is integrated into another. A holistic design provides for the joint integrated use of high-quality and quantitative methods in order to comprehensively evaluate this or that program. In this case, both groups of methods have equivalent status. The transformational design is in the case when different methods are used together to fix value views, which are subsequently used for the reconfiguration of the dialogue, whose participants adhere to various ideological positions.

What is a "clinical study"?

Clinical study - scientific research involving people, which is carried out in order to assess the effectiveness and safety of a new drug or expanding the indications for the use of the already known drug.

Clinical studies around the world are an integral stage of the development of drugs, which precedes its registration and a wide medical application. During clinical studies, the new drug is studied to obtain data on its efficiency and safety. Based on these data, the authorized health authority decides on the registration of the drug or refusal to register. The drug that has not passed clinical studies cannot be registered and launched.

When developing a new drug, it is impossible to do without clinical studies, since the extrapolation of research results in animals and on biological models per person is possible only in general, and sometimes impossible at all. For example, pharmacokinetics (how the medicine falls into the blood is distributed in the body and is derived from it) It differs in person even from pharmacokinetics at primates. However, the analysis of preclinical studies is very important to assess the likelihood of the development and nature of side effects, calculating the starting dose to study the properties of the drug in humans.

Clinical studies can only be initiated after encouraging results during preclinical research (research on biological models and laboratory animals), as well as the approval of the ethical committee and the positive decision of the authorized health authority of the country where research is planned.

Initially, the experimental drug is studied with the participation of a small number of patients and / or healthy volunteers. As the data on its safety and efficiency accumulates, the number of patients involved in the study increases, and the drug itself is compared with already known and widely used in medicines in medical practice.

Types of clinical studies

The first way to classify clinical studies - on the presence of interference in the usual tactics of patient maintaining, that is, in standard procedures for surveys and the treatment of the patient.

Observation (observational) study is a clinical study in which the researcher collects data by simply observing events in their natural flow, without interfering in them actively.

An non-interventional study ("Research without intervention") is a study in which the drug is prescribed in the usual way in accordance with the conditions set out in the permit for market realization. The question of the "attribution" of the patient to a specific treatment strategy is not solved in advance in the study protocol. This issue is solved in accordance with the existing practice, and the appointment of the drug is clearly separated from the decision on the inclusion of the patient in the study. No other diagnostic or monitoring procedures for patients are applied, and epidemiological methods are used to analyze the data collected data.

Interventional study - a study of new, unregistered drugs, immunobiological tools, medical equipment or a study in which drugs, immunobiological agents, medical appliances are prescribed or applied by a way different from the conditions set out in the registered instructions for use (whether new testimony, new Dosage of the drug, a new way of administration, a new way of application or a new category of patients).

The criterion for another method of classification is the purpose of the study. This classification method was proposed by the US National Institute of Health (The U.S. National Institutes of Health (NIH)) and highlights six different types of clinical studies:

• Preventive research (prevention trials) are held to find the best ways to prevent diseases in people who have never suffered from them, or to prevent the recurrence of the disease in patients. In such studies, drugs, vaccines, vitamins, minerals, changes in lifestyle can be studied.
• Screening Trials (Screening Trials) are held to find the best way to identify certain diseases or states.
• Diagnostic studies (Diagnostic Trials) are held to find the best way to diagnose a certain disease or state.
• Therapeutic studies (Treatment Trials) are held to study the efficiency and safety of experimental drugs, new combinations of drugs or new methods in surgery or radiation therapy.
• Quality of Life Trials (Quality of Life Trials) is held to explore ways to improve the quality of life of patients suffering from chronic diseases.
• Advanced access programs (by exceptional circumstances - Compassionate Use trials or Expanded Access) involve the use of an experimental drug in patients with serious or threatening life of diseases that cannot be included in a clinical study because they do not comply with the inclusion criteria. Usually, patients are involved in such programs, for the treatment of diseases of which there are no effective methods of treatment, or those who tried all the standard, well-known treatments, and which they did not help.

Design of clinical studies

The design of the study is a general study plan, a description of how research will be conducted.

The main types of observation studies are a cohort study and study "case-control" and others.

• In a cohort study, the dedicated group of people (cohort) is observed for some time. The condition of patients in different subgroups of this cohort, those who have been subjected or subjected to (or subjected to varying degrees) to the treatment with the studied drug are compared. In a prospective cohort study, the study plan is first drawn up and the procedure for collecting and processing data is determined, then cohorts are made, a study is carried out and the data obtained is analyzed. In a retrospective cohort study, the cohort is selected by archival records and trace the health of patients since the beginning of the patient's observation to the present.
• In the "case-control study", people with a certain disease with people from the same population that do not suffer from this disease to identify relationships between the clinical outcome and the preceding impact of certain robust factors are compared.

There are other types of observation projects - for example, Cross-Sectional Observational Study (simultaneous epidemiological study) and others.

The reference design of clinical studies are randomized controlled double-blind research.

The randomization procedure means that patients are distributed in groups of treatment randomly and have the same opportunity to obtain a studied or controlling preparation. The prescribed treatment prescribed by the patient usually has an effect regardless of whether it receives an active drug or not. The placebo effect should be taken into account. Today, two main control technologies are applied - placebo control and active control. Placebo-control means that patients in the control group give placebo - a product that does not contain an active principle, which in shape, color, taste, the smell fully imitates the studied drug. If the active method of treatment is applied to control, then the preparation studied is compared with the already known and widely used therapy (the so-called "gold standard").

Purpose Patients in the Placebo Control Group is associated with certain ethical problems, because it may limit their right to receive a better way to treat today. The possibilities of using placebo are limited. The Helsinki Declaration of the World Medical Association (VMA) determines that placebo is used only in two cases:

• first, if the effective method of treating the disease does not exist,
• secondly, if convincing scientifically substantiated methodological reasons for the use of placebo to assess the effectiveness or safety of the drug and patients receiving placebo or not receiving any treatment will not be at risk of causing serious or irreversible damage to their health.

Psychological, or so-called subjective factors play great importance when conducting clinical studies. For example, knowledge of the patient that he receives therapy with an active drug may affect the safety assessment and effectiveness of therapy. The researcher, convinced of the advantages of one of the compared drugs, may involuntarily interpret in its benefit of improved patients or try to prescribe a patient with a more severe disease, which he considers more efficient. To minimize the influence of subjective factors, use the blind method of conducting research.

A study in which the patient does not know, and the researcher knows what treatment is obtained by a patient, called simple blind. If neither the patient nor researcher know about the prescribed treatment, such a study is called double blind.

Blind studies allow minimizing the possibility of deliberate distortion, and unintentional - distribute between groups in an equal proportion.

Protocol of clinical research

The protocol is a document that describes the goal, tasks, a scheme, methodology, statistical aspects and the organization of the study. Any clinical study begins with the development of the Protocol. This is the most important document of the clinical research.

Having studied the Protocol, authorized health authorities and ethical committees assesses the adequacy of the scientific tasks and methodological approaches, the effectiveness of measures to protect the rights of research participants and decide on the possibility of a clinical study. During the study, the Protocol serves as a guide for researchers. It allows you to unify research centers around the world. After the end of the study, the protocol is the basis for holding statistical analysis and the document, on the basis of which the study test auditors and inspectors of authorized health authorities.

The Large Study Protocol may be developed for several years, not only sponsor employees, but also external consultants take part in the work on it.

Informed consent

Informed consent is a process that allows the patient or a healthy volunteer to freely confirm its desire to participate in a clinical study. An informed consent is also called a document that signs research participants (patient and researcher). The researcher's doctor informs the patient about all aspects of clinical research that may affect the decision to participate in the experiment (benefits, risks, time costs, possible side effects, etc.). Therefore, such consent is called informed. After the potential participant of the study explained all aspects of participation in a clinical study, the researcher gives the patient written information, which describes the details of the study (duration, procedures, risks, potential benefits, etc.). Once again, after examining the document, the participant decides, it is worth a consent to him or not.

A student of the study at any time can get out of the study without explaining the reasons.

Power research

Planning a clinical study, the sponsor company with the help of biomedical statistics specialists determines which number of patients need to be involved in the study to obtain a statistically significant result showing the difference in the effectiveness of compared therapy. The number of patients is determined before the start of the study, the cost of the study depends on it. Based on the cost of the sponsor, decides on the expediency of the study.

The number of patients needed to obtain a statistically significant result depends on the disease studied parameters, design, etc. For example, to show the effectiveness of the new drug in the treatment of incurable metastatic kidney cancer in a slavebocontrollable study, it is necessary much less patients than in a slave-controlled study of well-healing ovarian cancer. The fact is that if the patient can recover and without treatment, the spontaneous cases of improvement will "compose" the effect of therapy. To allocate exactly the part of patients who helped the drug, you need to score a large number of patients and separate them from those who recovered due to standard treatment. If the state of health of patients without treatment is immediately deteriorating sharply, the effect of therapy will be visible in a small group, the state of the health of those who receive effective treatment will not deteriorate immediately.

The characteristic of the study that allows you to identify the clinically important differences between the studied drug and the preparation of comparison (for example, in efficiency), if any actually is called the power of the test. The more patient sample, the greater the power of the test.

To reliably show a small difference, you need to dial more patients. However, increasing the number of patients, it is possible to statistically prove the presence of so small differences that will no longer have clinical significance. Therefore, it distinguishes statistical and clinical significance.

Phases of clinical studies

Preclinical studies include in vitro studies (laboratory tests in tubes) and studies in vivo (research on laboratory animals), during which various doses of the test substance are investigated to obtain preliminary data on pharmacological properties, toxicity, pharmacokinetics and metabolism of the studied drug. Preclinical studies help pharmaceutical companies understand whether to explore the substance further. Studies involving people can be started if the data obtained during preclinical studies prove that the drug can be used to treat the disease if the drug is sufficiently safe and the study does not expose people with unnecessary risk.

The process of developing a drug is often described as a consistent conduct of four phases of clinical studies. Each phase is a separate clinical study, several studies may need to register a drug within the same phase. If the drug successfully passes the tests in the first three phases, it receives a registration certificate. Studies IV phase are post-registration studies.

Phase I.

In the phase I studies, I usually participate from 20 to 100 healthy volunteers. Sometimes high toxicity of the drug (for example, for the treatment of cancer and AIDS) makes such research in healthy volunteers unethical. Then they are carried out with the participation of patients who suffer from a corresponding disease. Typically, phase I studies are carried out in specialized agencies, where there are necessary equipment and specially trained personnel. Phase I studies can be open, they can also use such a control method as control of the original state. In addition, they can be randomized and blind. The purpose of the I phase I studies is to establish portability, pharmacokinetic and pharmacodynamic parameters, and sometimes and give a preliminary safety assessment.

During phase I, indicators such as absorption, distribution, metabolism, excretion, as well as the preferred form of application and a safe dosing level are investigated. Phase I usually lasts from a few weeks to 1 year.

For participation in the study, a remuneration is paid.

There are various types of phase i:

Single Ascending Dose Studies, Sad (Single Ascending Dose Studies, Sad) is studies in which a small number of patients is introduced one-only dose of the drug under study during the entire time that they are under observation. If no undesirable reactions and pharmacokinetic data corresponds to the expected safety level, the dose increases and the following group of participants is obtained and this enlarged dose receives. The introduction of the drug with an escalation of doses continues until the pre-planned levels of pharmacokinetic security were achieved or unacceptable unwanted reactions will be detected (it is said that the maximum allowable dose is achieved).

Studies of multiple growing doses (Multiple Ascending Dose Studies, Mad) are studies that are conducted to better understand the pharmacokinetics and pharmacodynamics of the drug at repeated administration. During such studies, a group of patients receive low doses of the drug repeatedly. After each administration, blood and other physiological fluids are taken to evaluate how the medicine behaves in the human body. The dose gradually rises in the following groups of volunteers - to a predetermined level.

Phase II.

Assessing pharmacokinetics and pharmacodynamics, as well as the preliminary safety of the drug under study during phase I studies, the sponsor company initiates phase II studies at a greater population (100-500 people).

Phase II Studies Design C may be different, including controlled research and research with the control of the initial state. Subsequent studies are usually carried out as randomized controlled to assess the safety and efficacy of the drug under a certain indication. Phase II studies are usually carried out on a small homogeneous population of patients selected for hard criteria.

An important goal of these studies is to determine the level of dosing and a drug treatment diagram for phase III studies. Doses of the drug that receive patients in phase II studies, usually (although not always) lower than the highest doses that were introduced by participants during phase I. An additional task during phase II studies is an assessment of possible endpoints, the therapeutic reception scheme ( Including related drugs) and the definition of a targeted group (for example, a light form against heavy) for further studies during phase II or III.

Sometimes phase II is divided into phase IIa and phase IIb.

Phase IIA is trial studies planned to determine the level of safety of the drug on selected groups of patients with a certain disease or syndrome. The objectives of the study may include the determination of the sensitivity of patients to various doses of the drug, depending on the characteristics of the patient group, reception frequency, dose, etc.

Phase IIB is clearly regulated studies planned to determine the efficiency and safety of the effect of the drug on patients with a specific disease. The main task of this phase is to determine the optimal level of dosing for the III phase.

In some studies, phase I and II are combined, so that are tested both efficiency and the safety of the drug.

In phase II, it is necessary to preserve the control group, which in the composition and number of patients does not differ from the group receiving the studied drug. Patients in two groups must be comparable by sex, age and preceding background treatment. In this case, the efficiency and tolerability of the new drug is compared either with placebo, or with another active drug, which is the "gold standard" in the treatment of this disease.

Phase III

Phase III studies are randomized controlled multicenter studies involving a large population of patients (300-3,000 or more, depending on the disease). These studies are planned in such a way as to confirm the safety and efficacy of the drug in phase II pre-evaluated during phase II for a certain point in a particular population. The studies of the phase III may also study the dependence of the dose effect of the drug or the drug when using a wider population in patients with diseases of varying severity or in combination with other drugs.

Sometimes research III phases continues when the documents for registration in the appropriate regulatory authority have already been filed. In this case, patients continue to receive a life-saving drug until it is registered and will not go on sale. To continue research, there may be other reasons - for example, the desire of the sponsor company to expand the testimony for the use of the drug (that is, to show that the drug works not only with recorded indications, but also with other testimony or other groups of patients, as well as obtain additional information About security). Studies of this kind are sometimes classified as phase IIIB.

Confirming the effectiveness and safety of the drug during phase III studies, the company forms the so-called registration dossier of the drug, which describes the methodology and results of preclinical and clinical studies of the drug, the peculiarities of production, its composition, expiration date. The combination of this information is the so-called "registration dossier", which is submitted to the authorized health authority that registers (in each country - its own).

the drug is more effective than the well-known drugs of similar action,

it has better tolerance with comparable with already known drugs,

effective in cases where treatment already known drugs is unsuccessful,

more economically more profitable

easy to use

has a more convenient dosage form

it has a synergistic effect in combination therapy, without increasing toxicity.

Phase IV.

Phase IV is also known as post-registration studies. These are studies conducted after registering the drug in accordance with the approved testimony. These are studies that have not been required to register the drug, however, it is necessary to optimize its use. The requirement to conduct these studies can proceed from both the regulators and the sponsor company. The purpose of these studies may be, for example, the conquest of new markets for the drug (for example, in case the drug has not been studied for interaction with other drugs). An important task of phase IV is to collect additional information on the safety of the drug on a sufficiently large population for a long time.

The IV phase objectives may also be an assessment of such treatment parameters as treatment time, interaction with other drugs or food, comparative analysis of standard treatment courses, analysis of applications in patients of various age groups, economic indicators of treatment and long-term treatment results (decrease or increase The mortality rate among patients who are long-receiving given drug).

In addition to interventional studies of the IV phase (in which the drug is used on a registered indication, but the examination and patient management scheme is determined by the study protocol and may differ from routine practice), after approval of the use of the drug in the country, post-registration observational (non-interventional) studies can be carried out. In such studies, information is collected on how the drug is applied by doctors in their daily clinical practice, which makes it possible to judge the efficiency and safety of the drug in the conditions of "real life".

If, during the research of the IV phase or post-registration observational research, rare, but dangerous side effects, will be detected, then the drug can be removed from sale, its use can also be limited.

Phase division is generally accepted, but an approximate way to classify clinical studies, since the same study can be carried out at different phases. For example, despite the fact that pharmacological studies are usually carried out during phase I, many of them are initiated on each of the three phases, but it is still sometimes designated as phase studies I. The results obtained during the study often entail It is adjusting the entire research plan. For example, the results of a supporting therapeutic study may require additional pharmacological studies with human participation.

Therefore, the most preferred criterion of classification is the purpose of the study.

Design of medical clinical studies Concept design translated from English (Design) means plan, project, sketch, design. Methods of qualitative and quantitative research in evidence-based medicine. Clinical trials, definition, classification. Statistical analysis in evidence-based medicine. Levels of evidence and gradation recommendations of the results of clinical studies

Clinical trial - any prospective study in which patients are included in a group of interference or comparison to determine causal relationships between medical intervention and clinical outcome. This is the final stage of a clinical study, in which the truth of the new theoretical knowledge is checked. Design KI - a way to conduct a scientific research in the clinic, that is, his organization or architecture.

The type of design KI is a set of classification features that correspond to: 1) certain types of clinical tasks; 2) research methods; 3) methods of statistical processing of results.

Classification of research on design Observation studies (observation) is a study in which one or more patient groups are described and observed according to certain characteristics, and the researcher collects data by simply observing events in their natural course, without interfering in them actively; Experimental studies - the results of the intervention (drug, procedure, treatment, etc.) are estimated, one two or more groups participate. There is a subject of research.

1. Observational ↓ Descriptive analytical ↓ reports on case-monitoring cases of cohort 2. Experimental ↓ clinical trials

The most important requirements for medical research is the right organization (design) of research and a mathematically sound method of randomization. Clearly designated and observed criteria for inclusion and exclusion from the study. The right choice of case outcome criteria under the influence of treatment and without it. Research site to continue research the correct use of statistical processing methods

General principles of classical scientific research. Clinical Tests Controlled - Comparison of the drug or procedures with other drugs or procedures are more common, the likelihood of identifying differences in treatment is more uncontrollable - the experience of using the drug or procedure, but without comparison with another treatment option - it is distributed, less reliably-convergence to compare procedures more than for comparing the drug

Types of clinical issues that face a doctor when assisting the patient with the main categories of clinical issues are: prevalence of diseases, risk factors, diagnosis, forecast and treatment efficacy. Deviation from the norm - healthy or sick? Diagnosis - How accurate is the diagnosis? Frequency - How often does this disease occur? Risk - What factors are associated with an increased risk of the disease?

Forecast - What are the consequences of the disease? Treatment - How will the course of the disease change in treatment? Prevention - Are there any methods for preventing the disease in healthy? Is the course of the disease improving if it is an early declaration and treatment? Cause - What factors lead to the disease? Cost - how much is the treatment of this disease?

Types of Medical Studies Systematic Reviews, Meta-Analysis Randomized Clinical Studies (RCI) Cohort Studies Study Case-Control Series, description of one case study in vitro and animals

Systematized reviews (CO) is a scientific job, where the object of the study is the results of a number of original research on one problem, i.e., the results of these studies are analyzed using approaches that reduce the possibility of systematic and random errors; They are a generalization of the results of various studies on a given topic and are among the most "readable" options for scientific publications, since they allow you to quickly and most fully get acquainted with the problem of interest. Objective CO - weighted and impartial study of the results of previously conducted studies

A high-quality systematic review reviews the results of original studies on one problem or system, but a statistical analysis has not been carried out.

Meta-analysis - the top of evidence and a serious scientific study: a quantitative assessment of the total effect established on the basis of the results of all scientific research (H. Davies, Crombie I. 1999); Quantitative systematic review of literature or quantitative synthesis of primary data for obtaining total statistical.

Randomized controlled tests (research) - RCI RCI - in modern medical science are a generally accepted standard of scientific research to assess clinical efficacy. Randomization is a method used to form a sequence of accidental assigning participants in testing groups (RAND - Franz. - case). RCI - Criteria for assessing treatment

Structure of research at RKK 1. The presence of the control group 2. Clear selection criteria (inclusion and exceptions) of patients 3. Inclusion of patients to research to randomization in groups 4. Random method of distribution of patients by groups (randomization) 5. "Blind" treatment 6. " Blind "evaluation of the results of treatment

Study of the study - presentation of results 7. Information on complications and side effects of treatment 8. Information on the number of patients who retired during the experiment 9. Adequate statistical analysis, there are references to the use of the article, programs, etc. 10. Information about the size of the detected effect and statistical research

RCI - a comparison of end results should be carried out in two groups of patients: the control group - treatment is not carried out or the standard, traditional (usual) treatment or patients receive placebo; A group of active treatment - treatment is carried out, the effectiveness of which is investigated.

Placebo (Placebo) is an indifferent substance (procedure) to compare its action with the effects of this medicine or other intervention. The placebo is used when using a blind method so that participants do not know what treatment to them is appointed (Maltsev V., et al., 2001). Placebo-control technology is ethical in cases where the subject does not receive significant damage, going around without drugs.

Active control - a medicine is used, which is effective relative to the test indicator (the Gold Standard preparation is more often used - well-studied, long and widely used in practice).

Homogeneity of compared groups - patient groups must be comparable and homogeneous by: clinical features of the disease and concomitant pathology age, floor, racial affiliation

Representativeness of groups The number of patients in each group should be sufficient to obtain statistically reliable results. The distribution of patients in groups should occur randomized, that is, by the method of random sample, which makes it possible to eliminate all possible differences between compared groups, potentially capable of affecting the result of the study.

The blinding method is to minimize the conscious or unconscious possibility of influencing the results of the study by its participants, i.e., in order to eliminate the subjective factor, the "blinding" method is applied in evidence-based medicine (eng. Blinding).

Types of "blinding" Simple "blind" (Single - Blind) - about belonging to a certain group does not know the patient, but the doctor knows; Double "blind" (DOUBL - BLIND) - The sick and doctor do not know about the belonging to a certain group; Troopo "Blind" (Triple - Blind) - About belonging to a certain group do not know the patient, doctor and organizers (statistical processing) Open study (Open - Label) - All participants in the study are aware

The results of the RKK - should be practically significant and informative: this can be carried out only with a sufficiently long observation of patients and a low number of patient failures from continuing participation in the study (<10%).

The true criteria for the effectiveness of treatment are primary - the main indicators related to the vital activity of the patient (death from any reason or the main - studied disease, recovery from the test disease) - secondary - improving the quality of life, reducing the frequency of complications, facilitating the symptoms of the disease - surrogate (indirect), Tertiary - the results of laboratory and instrumental studies, which are supposed to be associated with true end points, i.e. with primary and secondary.

Randomized clinical studies - objective criteria of finite results should be used: mortality from this disease Total mortality rate of the development rate of "large" complications The frequency of repeated hospitalization of the quality of life

A cohort study (Cogort Group) is selected a group of patients for a similar feature, which will be traced in the future begins with the assumptions of the risk of a group of patients: - exposed to the risk factor-not to the exposure to the risk factor prospective in time (in the future) determination of the desired factors in The exhibited group answers the question: "Do people (in the future) sick if they are exposed to the risk factor? " Basically, promotional, but there are and retrospective. Control over both groups is carried out equally evaluating the outcomes of historical cohort - selection of cohorts by disease histories, and observation is currently.

Study Case - Control Increase, is organized to identify communication between any risk factor and clinical outcome. In such a study, the proportion of participants who experienced the harmful effects in two groups, in one of which developed, and the clinical outcome was not observed. Basic and control groups relate to the same risk population. Basic and control groups should be equally exposed to the classification of the disease at T \u003d 0. Impact is measured equally in both groups may be the foundation of new scientific research, theories.

Study Case - Control (Retrospective): - At the beginning of the study, the outcome is not known - cases: the presence of a disease or outcome - control: the absence of a disease or outcome is the answer to the question: "What happened? »It is a longitudinal or Longitudual study

Study of a series of cases or descriptive study Description of a series of cases - a study of the same intervention in individual sequentially included patients without a control group for example, a vascular surgeon may describe the results of the reversal of carotid arteries in 100 patients with brain ischemia describes a certain number of features of interest in the observed small groups Patients relatively short period of research does not include any research hypotheses does not have control groups precedes other studies this type of study is limited by data on individual patients