Chapter 3. MEDICAL INFORMATION SYSTEMS
4.2. Basic principles and provisions of evidence-based medicine Pharmacotherapy (treatment of patients with medications) has
been known for a long time. Domestic pharmacotherapy has always been distinguished primarily by individual approach and democratic principles. The famous Russian clinician B. Votchal shrewdly remarked in 1963: "The doctor must conduct a ship of pharmacotherapy through a narrow fairway between the shallows of excessive caution and the rocks of reckless courage."
Prior to the advent of "evidence-based medicine", it was
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thought that medicine was the second most accurate science after religious service. However, now evidence-based medicine is the criterion for diagnosis, treatment and prevention.
It is a well-known fact that treatment options have now grown dramatically due to the large number of new pharmaceuticals, and the effectiveness of pharmacotherapy has grown significantly less.
The practitioner receives a wide array of medical information on the use of pharmaceuticals in various internal diseases. In this regard, a new approach to the evaluation of effectiveness of treatment and diagnosis of diseases according to evidence-based medicine has been developed.
Evidence-based medicine became famous at the turn of the 1980-1990s through the work of Canadian researchers at McMaster University (Toronto). In 1998, a monograph was published by the leading cardiologists in Canada, the United States, and the United Kingdom under the name Evidence-Based Cardiology. Evidence- based medicine is rooted in medical information, the reliability of which is beyond doubt; it aims to effectively treat a particular patient. The new clinical medicine program differs from the previous ones in that it reduces the influence of the subjective factor on the choice of diagnosis and treatment criteria according to the recommended algorithms, which requires the doctor to critically evaluate the views of different experts and the results of clinical studies and systematic reviews.
Evidence-based medicine is a new field of medicine characterized by the continuous training of practitioners based on the results of many placebo-controlled trials.
Evidence-based medicine is a strategic direction of modern medical science and practice, which is based on perfect scientific information and is aimed at increasing the level of scientific research, significantly improving the diagnosis, prevention, treatment and prognosis of human diseases, optimization health care systems.
There are many standards (in the form of lists of medical services) and treatment protocols (detailed guidelines for therapeutic and diagnostic tactics) in Ukraine, but the qualitative level of these developments is not in line with international ones,
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and their implementation in clinical practice is limited by pilot projects. The principles of evidence-based medicine and clinical epidemiology should be based on the provision of medical care.
However, the gold standard in treatment control are randomized controlled trials (RCTs) with double or triple-blind controls.
Evidence-based medicine aims at solving the following tasks:
1. To standardize the activities of scientists, doctors and organizers of health care under the principles of evidence-based medicine.
2. To increase the effectiveness of pharmacotherapy and treatment of acute diseases and syndromes (especially urgent conditions), and in the case of chronic diseases – to stabilize long- term remission, reduce mortality and improve the quality of life of patients.
3. To increase the safety of treatment and reduce the risk of complications and aggravation of the disease through the rational prescription of medicines and treatments.
4. To optimize the activities of national health systems.
5. To optimize the cost-effectiveness of treatment by choosing less expensive and, at the same time, sufficiently effective medicines, diagnostic and treatment methods.
Furthermore, in a figurative sense, evidence-based medicine is designed to release medical science and medical practice from outdated and ineffective methods of diagnosis and treatment, with a practical test of scientific hypotheses as to the development of various diseases.
In this case, more than 50 years ago, one of the heroes of the book "Children of Hippocrates" by Giuseppe D'Agatha said: "Until all the doctors will not be able to supply an identical diagnosis of the same patient and prescribe the same treatment, medicine cannot be considered seriously as a science." Probably, it is very difficult to define the problem of evidence-based medicine more accurately.
The novelty of evidence-based medicine is that it has developed criteria for proving the results of clinical trials for numerous methods of diagnosis, prevention and treatment, as well as new methods of management of the health care system.
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Therefore, according to the concepts of evidence-based medicine, every responsible decision of a doctor or a health care officer should be based only on scientific facts, which excludes subjectivity in medicine.
One of the tenets of evidence-based medicine is the assertion that the most cautious and critical approach to medical decision- making is required. Evidence-based medicine does not replace clinical judgment.
It is known that knowledge acquired by the doctor over time will inevitably be forgotten. The current system of postgraduate continuing education in Europe, USA, Russia, and Ukraine is inefficient. At lectures, students and interns have little to learn about the material they read, and they actually learn more during scientific and practical conferences. Therefore, it is advisable to print tutorials or reference books on evidence-based internal medicine with additions every 1-2 years.
According to the Swedish Council on Technology Assessment in Health Care, the quality of evidence depends on the following important requirements:
1. A randomized controlled trial is the most objective study since the possibility of a systematic error is much less than in other studies. They are carried out on a large population of patients, often in different countries with prolonged (1-25 and more years) observation. In these cases, placebo or "pacifier" (indifferent therapy) or drugs with known activity are often used.
2. Cohort studies are conducted with the formation of two or more patient groups when observations have been made for years or decades. In some cases, cohort studies have an advantage over RCTs, but their findings will always be less valid.
3. Cross-sectional studies are conducted by interviewing healthy people or patients to determine the rating of the study method or the frequency of use of the drug.
4. The case-control study is first conducted with the formation of a group of persons with individual cases of a relevant disease or clinical effect, and only then a control group is formed from persons without such disease or condition, but similar in important prognostic characteristics (age, sex, presence of concomitant diseases, etc.).
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5. Describing a case or series of cases is a brief report of the successful treatment of patients or the occurrence of threatening adverse complications of pharmacotherapy. Although the evidence of such a message is considered as a weak evidence, it is necessary due to its promptness.
Grades and levels of evidence are presented in the introduction of the manual.
Clinical epidemiology is the methodological foundation of evidence-based medicine. It studies the patterns of spread of any disease and also predicts it for each individual patient based on a study of the clinical course of the disease. Clinical epidemiology is conducted only on humans, not animals.
Clinical epidemiology provides evidence-based medicine with the necessary methods of biostatistics, objective criteria for the reliability of objective laboratory and instrumental studies, and methods for generalizing them. In addition, clinical epidemiology studies the complications and prognosis of diseases, the results of many center-placebo-controlled studies to determine the objectivity of different treatments and side effects of medications.
The essence of clinical epidemiology in the west is defined as five "D":
1) Death of a patient, especially when it is premature;
2) Disease, which is always perceived by the patient as a dangerous condition;
3) Discomfort, such as pain, nausea, shortness of breath, edema, etc.
4) Dissatisfaction, i.e., emotional reaction to the disease;
5) Disability, i.e., the inability of the patient to perform normal activities at home, at work, on vacation.
The disease should be considered as a hypothesis that must pass clinical trials.
A practitioner based on clinical epidemiology should:
- constantly receive intellectual pleasure and confidence (instead of wonder and disappointment);
- receive informative and effective medical information (what drugs can be used to improve the effectiveness and safety of treatment);
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- obtain a single scientific foundation, based on well-organized and reliable clinical trial results;
- judge the extent to which his/her efforts to combat biological, physical and social factors are able to positively influence the results of treatment (the doctor is convinced what he/she is able to do and what is not effective);
- evaluate the financial capacity of the patient and the society, if it can help him/her.
Therefore, the main objective of clinical epidemiology should be considered as an active pursuit of clinical observation and data analysis techniques that ensure that correct and adequate decisions are made in the treatment of patients with due regard to economic provision.
The following scientific studies are distinguished:
experimental (in which the effectiveness of treatment is studied) and observational ones. In turn, observational studies are divided into prospective and retrospective studies; single (transverse) and longitudinal (over a period of time). The case-control study provides a retrospective assessment of different patient groups.
RCTs are divided into the open and blind (the patient is not informed of the type of treatment). A double-blind study is when neither the doctor nor the patient knows what treatment is being performed. Blind studies belong to class I. Well-planned open experimental research, prospective and retrospective observational studies are in class II, and studies that make mistakes or when the individual experience of a scientist is taken into account are in class III.
The search for new medications is initially performed on experimental animals (preclinical studies). After completion of the experimental studies, their results are submitted to the State Pharmacological Center of the Ministry of Public Health of Ukraine, in the USA – the Food and Drug Administration (FDA), in Europe – the European Agency for the Evaluation of Medicinal Products (EMEA) and others. On average, it takes more than 12-15 years to develop a new medication from the search stage to full approval. Approximately 1 out of 15 tested substances undergoes trial in Phase III and is approved. In 2002, the International
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Foundation for Clinical Research (IFCC), a non-governmental organization, was set up to assist in establishing an appropriate clinical trial framework (organization of exhibitions, seminars, symposia, project creation, research programs, material funding for research, and support of fund members).
Clinical trials are conducted in 4 phases:
The first phase is conducted on 20-80 healthy volunteers, usually young men, in order to establish the dosage range of the drug, its tolerability and safety.
The second phase of the clinical trial is the first experience of using the active substance in patients with the disease. The main goal is to prove the clinical effectiveness in the study of 200-600 patients, to determine the levels of therapeutic doses of the substance, dosage regimens.
The third phase of clinical trials involves rigorous control studies that are conducted to determine the safety and efficacy of the active substances in the conditions closest to their use for patient therapy. More than 2.000 (over 10.000 are defined as mega- studies) patients are involved in such trials. Researchers study the action of the substance in combination with other drugs, conduct controlled studies with placebo, reference drug, or standard treatment. Uncontrolled clinical trials (blind and open) may also be performed.
The fourth phase of clinical trials (post-marketing studies) is conducted after registration (licensing) of the medicinal product in order to obtain even more information regarding its safety and efficacy.
During the research, the following is determined:
- improvement of dosage regimens and dosing schedules;
- interaction with food or other medicines;
- influence of individual factors of the medicinal product on the use and the like.
To supervise the treatment, researchers use the method of objective control – comparative study, randomization, blinding masking.
To determine the effectiveness of the study, researchers use a placebo, which is a pharmacological drug that has no active
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ingredients, and in its appearance does not differ from the main medication.
In the last decades in the United States, the cost of research and development of one medication has increased dramatically (from $54 million in 1976 to $450 million in 2001, an increase by 8 times in 25 years).
The ethical principles of such trials were formulated after the Second World War at the Nuremberg Trial (when the fascists were brought before the court). The quality of research in the CIS countries does not meet the generally accepted criteria of GCP (good clinical practice). For monopolized ethical control, there are biomedical ethics committees. The patient must consent to his/her inclusion in scientific research, and this is documented.
However, practical medicine is not only medicines, but also surgeries, various procedures, supervision of patients, organization of health care. These treatments are also used in evidence-based medicine.
In the West, the problem of provability is unambiguously resolved. Unfortunately, in Ukraine there are still mostly open, uncontrolled, non-randomized clinical trials, and therefore their value is low. Such studies do not answer the question as to the effect of pharmacotherapy on patients' survival, quality of life, risk of complications, and the like.
It should be emphasized that food supplements are not subject to clinical trials as they are not medicines. Of these, the most effective are those that include vitamins and trace elements, which have a positive effect on metabolic processes in the human body.
We know that practitioners have to deal with a huge volume of medical information. About 6.000 medical journal articles are published daily in the world. The MEDLINE World Bibliographic Database already has over 12.5 million abstracts of medical articles in its collections. Indeed, no doctor is able to read (pass through) such information. To this end, experienced specialists in the profile make clinical (not medical, as we have) recommendations. Clinical guidelines are very serious medical records that reflect the technology of doctors’ actions in specific clinical situations. These should be the best standards of clinical practice to improve the
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quality of diagnosis, treatment and prevention of diseases, as well as to improve the performance of health care authorities. Evidence- based medicine prevents the use of ineffective methods of diagnosis and treatment. Therefore, clinical guidelines are one of the most important tools for improving the quality of care. It should be noted that clinical guideline as such is a very expensive document (it costs $500.000-750.000 to prepare and publish it in the United States.)
However, these costs are justified by the high cost- effectiveness. It is known that in Germany there are 100 new scientific recommendations every month, whereas there are already more than 5 thousand in the U.S. Clinical guidelines are easy to use, developed by modern methodology through generalization of the best international experience and knowledge, with the possibility of their use in clinical practice. These features outweigh the value of clinical guidelines over our methodological guidelines.
In Russia, the development of clinical recommendations is mainly done by enthusiasts – professional associations and expert groups.
In Ukraine, clinical guidelines have not yet been established, and the guidelines Standards of Inpatient Diagnostic and Treatment Process, developed in 1999, are outdated and do not cover the achievements of evidence-based medicine.
The protocols for providing medical care to patients with diseases of the internal organs (the collection of orders of the Ministry of Public Health of Ukraine as of December 2, 2004 No.
593; as of June 13, 2005, No. 271; as of July 3, 2006, No. 436 and as of October 12, 2006, No. 676) have significantly increased effectiveness of diagnosis, treatment and prevention of diseases.
Clinical recommendations are based on confidence levels A, B, C, and D:
A – high reliability;
B – moderate reliability;
C – limited reliability;
E – low reliability.
At present, about one-third of clinical guidelines have A- level reliability, and all others are based on less qualitative studies.
It should be emphasized that the highest level of evidence is
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provided by RCTs. In addition, in some cases, especially in the assessment of adverse reactions, the best level can be obtained from retrospective case-control or cohort studies.
Recently, meta-analysis of studies are often conducted – this is a special form of statistical analysis, which combines the results of many clinical trials of any treatment method. This approach provides high statistical power as compared to individual tests. In general, meta-analysis allows us to summarize information obtained from various sources with certain reliability (or without it).
The "gold standard" is often used in evidence-based medicine – a well-conducted clinical trial of the appropriate design and sample size, organized to evaluate the effectiveness of a drug. To do this, researchers use the known and the most effective pharmacological preparation.
Depending on the effectiveness, one can distinguish basic, special and additional treatment:
1) basic treatment allows to interrupt the course of the disease and promote healing;
2) special treatment allows to prevent and eliminate the possible exacerbation of the underlying disease or relapses of concomitant pathological processes, the manifestation of possible side effects of drugs under special indications;
3) additional treatment contributes to the follow-up care of the patient, often after discharge from the hospital.
It is a very important decision of the doctor to choose the method of patient's treatment, which should:
- interrupt the course of the disease and promote healing (basic treatment);
- prevent and eliminate the possible exacerbation of the underlying disease or the recurrence of concomitant pathology and adverse reactions of drugs (treatment under special indications);
- facilitate the follow-up of the patient after discharge from the hospital (additional treatment) through the use of adequate doses of pharmacological agents.
The cost and effectiveness of treatment is calculated as follows:
1. Researchers conduct an analysis of the minimum cost-
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effectiveness of therapy when treatment that requires less resources is considered more effective.
2. Cost-utility analysis allows monetary evaluation of the impact of any medical intervention, especially in diseases with high mortality, on the life expectancy in combination with its quality index.
3. Cost of profit analysis is a method of economic evaluation of the effectiveness of treatment, in which its cost and effectiveness are evaluated only in monetary terms when the cost is compared with the profit.
4. Cost-effectiveness assessment is the most common method in evaluating the cost-effectiveness of treatment. However, it has some drawbacks, especially when several criteria are used for the effectiveness of medical interventions, such as increasing life expectancy and improving quality through disease manifestations.
In evidence-based medicine, 4 of these methods for determining pharmacological analysis are used to select drugs from the group of analogues.
Quite often the doctor prescribes the patient cheap medications, or, conversely, expensive ones. That is why it is very important to carry out pharmacological analysis of medicines, which takes into account both the cost of medicines and the effectiveness of their treatment. This method is especially important when evaluating the effectiveness of expensive surgical methods of treating heart disease (aortic-coronary bypass grafting, balloon angioplasty and coronary artery stenting).
New methods of diagnostics and treatment of internal diseases are being actively developed. They should be compared to the
"gold standard", which is highly accurate.
Clinical trials of new drugs began in the late 1940s. During this time, more than 500.000 such tests were performed. However, many of these therapies described in the journal articles have remained ineffective and not applicable.
There are 3 categories of primary research:
1) experimental animal studies;
2) clinical trials in which pharmaceutical, surgical, radiation treatments are performed according to a special technique and