Double-blind placebo-controlled…

What is evidence-based medicine?

Blog of the clinic "Our time", Habr

Previously, it was partly easier for doctors. If you were sufficiently respected and authoritative, then no one doubted your methods of treatment. If the doctor said that it was necessary to regularly arrange bloodletting and apply lotions based on mercury compounds, then they did so. Medicine gradually developed, but until the middle of the XX century, treatment methods were based on the authority of individual well-known scientists and their students. Does your wife get hysterical and nervous very often? Is the child constantly acting up? No problem, there are wonderful lobotomobiles. They'll come home and fix everything.

The procedure was as follows: an ice pick was inserted into the patient's eye socket. A light hammer blow on the handle pierced the orbital wall. Then Freeman moved the knife from side to side, destroying the frontal lobes of the brain. The method is, of course, effective, as it was developed by respected people and was recommended to "violent", schizophrenics and people whose behavior disturbed others. People from violent became quiet and submissive invalids. Up to 6% died during the operation.

Dr. Walter Freeman and James Watts are planning a lobotomy to help a person cope with anxiety.

It is already now that we have GMP, GTP, GCP standards, ethical committees, double-blind placebo-controlled trials and everything else that allows us to develop the most effective treatment methods. Today we will talk about clinical trials and how evidence-based medicine works.

Ethics of human experiments

One of the main tragedies of the XX century is the Second World War. It has destroyed millions of families and claimed the lives of many people. Already after the Nuremberg trials ended, doctors and scientists around the world had a question about what to do with the results of criminal research within the German concentration camps and the Japanese detachment 731 in China. The latter was engaged in research of biological weapons on experimental prisoners of war. Many journals refused to publish papers that cited data obtained as part of Nazi experiments as sources. As a result, a consensus was reached. Most scientific communities have come to the conclusion that it would be wrong to give up the opportunity to save human lives. Despite the fact that the data were obtained in a completely monstrous way, they are valuable for medicine. Nevertheless, in the future, any medical research should be based solely on the principles of maximum safety and awareness for all participants.

For example, the death of many people during hypothermia experiments nevertheless served the development of modern methods of controlled hypothermia, which allows to increase the survival rate of patients with extensive myocardial infarction and ischemic strokes. The results of the criminal experiments of detachment 731 gave a lot of data, which later made it possible to develop effective protocols to combat the plague and other particularly dangerous infections.

Currently, clinical trials are conducted only after the evidence base is collected at the molecular and cellular level, and then on small and large animals. Preclinical studies depend on which models the studies are applicable on. In any case, before the stage involving people, maximum information is collected in order to reduce the risks for volunteers. Only after that, a detailed design of a medical study is developed, which must be approved by both experts from regulatory authorities and the ethics committee. The investigation of Nazi crimes within the framework of the Nuremberg Trials formed the basis of the ethical standards of the Nuremberg Code, on which most modern conventions in this area are based.

The basic principles of the Nuremberg Code

1. An absolutely necessary condition for conducting an experiment on a person is the voluntary consent of the latter. This means that the person involved in the experiment as a subject must have the legal right to give such consent; be able to make a free choice and not be influenced by any elements of violence, deception, fraud, cunning or other hidden forms of pressure or coercion; have sufficient knowledge to understand the essence of the experiment and make an informed decision. The latter requires that, before making an affirmative decision on the possibility of participating in a particular experiment, the subject should be informed about the nature, duration and purpose of this experiment; about the methods and methods of conducting it; about all the alleged inconveniences and dangers associated with conducting the experiment, and, finally, the possible consequences for the physical or mental health of the subject, which may arise as a result of his participation in the experiment. The responsibility and responsibility for determining the quality of the consent received lies with everyone who initiates, directs or is engaged in conducting this experiment. This is a personal duty and responsibility of each such person, which cannot be transferred to another person with impunity.

2. The experiment should bring positive results to society that are unattainable by other methods or methods of research; it should not be random, optional in nature.

3. The experiment should be based on data obtained in laboratory studies on animals, knowledge of the history of the development of this disease or other studied problems. Its holding should be organized in such a way that the expected results justify the very fact of its holding.

4. During the experiment, it is necessary to avoid all unnecessary physical and mental suffering and damage.

5. No experiment should be conducted if there are a priori grounds to assume the possibility of death or disabling effects on the subject; an exception may possibly be cases where medical researchers act as subjects during their experiments.

6. The degree of risk associated with conducting an experiment should never exceed the humanitarian importance of the problem that this experiment is aimed at solving.

7. The experiment should be preceded by appropriate preparation, and its conduct should be provided with the equipment necessary to protect the subject from the slightest possibility of injury, disability or death.

8. The experiment should be conducted only by persons with scientific qualifications. At all stages of the experiment, maximum attention and professionalism are required from those who conduct it or are engaged in it.

9. During the experiment, the subject should be able to stop it if, in his opinion, his physical or mental condition makes it impossible to continue the experiment.

10. During the experiment, the researcher responsible for conducting it should be ready to stop it at any stage if professional considerations, conscientiousness and caution in judgments required of him give reason to believe that the continuation of the experiment may lead to injury, disability or death of the subject.

Phases of clinical trials

Phases of drug trials, WHO illustration.

Phase 1

About 50 people.

Studies of early phases. The drug is administered to a small group of volunteers. Usually they are absolutely healthy young volunteers. What is being studied:

• Possible harm.

• Side effects.

• The optimal dosage.

Phase 2

Up to 500 people.

Expanded safety studies and the first data on the effectiveness of treatment. The drug is being studied in patients with the target pathology, usually without concomitant diseases. What is being studied:

• Is the drug effective for the treatment of pathology.

• Side effects.

• The drug is compared with a placebo.

Phase 3

Usually up to 1000 people, but it can be significantly more. The sample sizes can be different and depend on the variability of the main parameter studied and the expected effect of the drug, the size of the estimated differences in efficacy with the control drug or placebo. For example, a conditional drug should reduce the risk of death from the disease by 1:1000 per year. To reliably prove the effect of the drug, it will be necessary to conduct research for several years on samples of much more than 1000 people.

Confirmatory efficacy studies, comparison with other treatment methods. The concepts put forward at the previous stages are confirmed. This phase is usually carried out in different centers and countries. The drug is being studied on patients with target pathology, of different ages and with various concomitant diseases. What is being studied:

• Is the drug effective for the treatment of pathology.

• Effectiveness in comparison with other methods of treatment, as a rule, with one of the standards.

At phase 2, the question immediately arises — why a placebo? In fact, placebo-controlled trials are the cornerstone of evidence—based medicine. You can find a huge number of people who take homeopathic medicines and confidently declare that they are getting better. At the same time, this effect is subjective, perhaps a placebo would have the same effect, but this requires research. Therefore, the placebo effect is taken as a basis when checking the effectiveness of the drug, it is necessary to find out the size of the placebo effect and how much the developed drug exceeds the placebo.

Experiment with lemons

One of the first clinical experiments according to a relatively strict protocol was conducted in May 1747 by the military surgeon James Lind. On the British frigate Salisbury, the sailors began to have scurvy. Lind selected 12 patients, divided them into pairs and locked them in a separate forecastle. They were fed the same food as the others, but added something different to each group's diet:

1. A liter of cider daily.

2. 25 drops of vitriol elixir (most likely, it was a solution of sulfuric acid).

3. 6 tablespoons of vinegar before meals.

4. A glass of sea water daily.

5. 2 oranges and a lemon daily.

6. A paste of garlic, mustard, dried radish and myrrh oil.

As a result, the sailors from the fifth group returned to the general forecastle and began to help care for the rest of the patients.

Is a placebo ethical

It is not always possible to use placebo patients as a comparison group. For example, there are already working protocols for the treatment of oncopathology. They may not be perfect, but they allow statistically significantly prolong the patient's life. In this case, the ethics committee will not approve the use of placebo and active control in the form of a standard treatment protocol will be used instead. The Helsinki Declaration of the World Medical Association (WMA) defines that placebo is used only in two cases:

1. If there is no effective way to treat the disease.

2. If convincing, scientifically based methodological reasons are presented for using placebo to assess the efficacy 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.

The Tuskegee Experiment

So, in 1932, in the United States, the Department of Health began in the city of Tuskegee (J. James. Bad Blood: The Tuskegee Syphilis Experiment. New York: Free Press. ISBN 0-02-916676-4) a study of the natural course of syphilis in 399 African Americans. Scientists were interested in what would happen to people in the long term if they were not treated. The study also involved local African-American doctors and the Rosenwald Foundation, which paid part of the cost of treating patients. Not only were the patients not informed that they had syphilis, but they were also not told that they were participating in a clinical trial. It was assumed that patients would be monitored for 6-9 months, and only then they would begin receiving treatment. However, then the Rosenwald Charitable Foundation, due to lack of funds, refused to finance the study, and there was no money for the purchase of medicines.

In 1928, a similar study was already conducted in Norway, but it was retrospective, that is, it implied working with archives on cases of untreated syphilis. Immediately, scientists decided to conduct a prospective study, leaving patients without treatment at all, and only to observe the course of the disease. In 1947, it was discovered that penicillin could effectively treat syphilis, but the Tuskegee study was not discontinued, and the protocol was not changed. On the contrary, conditions were continuously deteriorating. In order to force patients to take CSF and go through a painful spinal puncture, they were sent letters that said that "this is their only chance to get special free treatment." In order for the subjects to give permission for an autopsy, the researchers promised to pay them the funeral costs.

As a result, the study was stopped only in 1972 due to the publication of details in the media. By the end of the experiment, 325 people out of 399 participants had died. 28 died from syphilis and 100 from its complications. In addition, 40 partners and 19 children who were born with congenital syphilis were infected. On May 16, 1997, President Bill Clinton made a public apology in Tuskegee, but there is still a problem of the poor African-American population of the United States trusting doctors and research programs. It was only after the middle of the 20th century that the Nuremberg Code and the Helsinki Declaration began to protect the basic rights of research participants. That is why there are now almost no studies that leave the patient without effective treatment. Almost always, these are clinical studies for comparison with existing methods of treatment. It is also possible to conduct a study with historical control when comparing with similar groups of patients in the past.

SARS-CoV-2 vaccine Research

Clinical trials of coronavirus vaccines started a year and a half ago. The design of the experiment suggested a classic variant — a double-blind randomized placebo-controlled trial. In this case, neither the doctor nor the patient knew what exactly was in the vial. This information is stored in encrypted form and is not known until the last stage, when all the data has already been collected and described. This procedure is called blinding and allows you to impartially evaluate the effectiveness of a drug or vaccine in all groups. Then an ambiguous situation developed. From an ethical point of view, there were no problems in using placebo at the start. If a person gets saline, then he will simply be sick "on general grounds." He does not receive the potential protection of the vaccine, like the rest of the population, but at the same time does not receive the potential risks from the new drug. Everything is fair. However, a few months later, when, due to the current epidemiological situation, it was decided to start scaling and mass vaccination with an incomplete third phase, the subjects found themselves in an ambiguous situation. Most of them participated in clinical trials in order to be the first to get a protective effect from covid, but now they risked getting a placebo, and at this time everyone outside the study could be guaranteed to get a real drug. According to the terms of the clinical trial, they had to wait for its completion to find out which group they were in and get a real vaccine, if it was a placebo.

Levels of persuasiveness of evidence by type of research.

The key difference between the concept of evidence-based medicine is that any treatment methods, drugs or vaccines must meet strict criteria. The beginning of evidence-based medicine was laid in 1979 in Canada, when the effectiveness of the intervention began to be evaluated in accordance with the quality of the evidence obtained.

The opinions of respected experts are great, but they are less significant than, for example, case-control studies. And even more insignificant against the background of randomized controlled trials, especially if they are conducted in different countries and by different teams.

At the top of the evidence are meta-analysis and systematic reviews. One of the most well—known and large organizations that deals with systematic reviews, mainly on randomized controlled CI, is Cochrane. They select scientific publications according to strict criteria of "quality", which include the design of the experiment, sample sizes and other parameters. Then, on the basis of the selected studies, a meta-analysis is prepared, which takes from 6 months to 2 years to prepare. On the basis of these studies, national clinical guidelines from different countries and treatment protocols are already being created.

And here in Russia there is a whole layer of problems associated with treatment methods that developed before the advent of evidence-based medicine. For example, the well—known zelenka — aniline dye "diamond green" - is still actively used only in Russia and some other countries. Most of the studies of its effectiveness were carried out only in vitro and do not meet the criteria of modern CI. Does this mean that the drug does not work? No, it doesn't. It's just very expensive to conduct research according to all the rules from scratch, and everything seems to be used anyway. Is it necessary to use drugs that may work in clinical practice? From the point of view of evidence—based medicine, no. As an alternative to the same zelenka or fucortsin, there are many transparent, non-irritating antiseptics that have passed all the necessary clinical studies.

In the same category automatically fall such popular drugs as oxoline ointment, which has no proven effectiveness in vivo, and all the "adored" fuflomycins, which are trying to treat everything. Fortunately, some have at least been removed from the Temporary Guidelines for the Treatment of coronavirus Infection. Although there are still many points that go against the research results. So, the same favipiravir in studies did not show any statistically significant efficacy. The use of plasma of patients who have been ill for the treatment of moderate and severe forms also did not show effectiveness in the published Cochrane meta-analysis.

Why Evidence-based Medicine Can Be Cheaper

Many believe that evidence—based medicine is expensive. These are necessarily some fashionable expensive drugs and expensive hardware methods of treatment. In fact, this is not the case. Let's simply compare the appointments of a conditional doctor from a conditional clinic/polyclinic and a doctor who strictly adheres to the principles of evidence-based medicine. Take the usual ARVI.

In a conditional clinic/polyclinic:

• Here are interferons drops in your nose.

• Plus eye drops in the same place (antibiotics).

• Interferons by candles rectally.

• Homeopathic pills to stimulate the immune system.

• An immunomodulator with a turbid mechanism of action that is not used anywhere else in the world.

• Three packs of different vitamins, and preferably with iHerb.

• Antibiotics from the first day of the disease, if the soul really asks.

• Antipyretic.

In the clinic of evidence-based medicine:

• Drink more fluids.

• If you have a sore throat, you can have ice cream or warm drink or lollipops with anesthetics.

• If the temperature is high and poorly tolerated, take an antipyretic.

• If you have a runny nose — saline solutions, if necessary, vasoconstrictor for 3 days.

In fact, many nosologies do not require something expensive and unique at all. It is enough just to apply one simple and possibly inexpensive method of treatment.

New treatments for epilepsy, migraines and cholesterol metabolism problems

Scientific method and evidence-based medicine have become the trend that regularly moves medicine and biotechnology forward. In the last 10 years, there has been a real breakthrough in the treatment of many pathologies. Doctors unite in their specialties into professional communities, gather at conferences and develop their clinical recommendations for their nosologies. These clinical recommendations are necessarily based on qualitative research.

Epilepsy

Modern treatment protocols for epilepsy now in some cases involve surgical treatment. Moreover, this approach significantly improves the chances of remission in this group of patients. Remission of epileptic seizures after surgical treatment is observed in 50-80%.

Thus, surgical intervention may be recommended if:

• The patient has tried at least 2 anticonvulsants correctly selected for this type of seizures, one at a time or in combination, but the seizures persist.

• Seizures begin in one area of the brain, the epileptogenic zone is determined.

• Seizures begin in an area that can be safely removed without causing serious complications, such as motor disorders, speech, memory or vision disorders.

• Seizures are caused by another problem in the brain, such as a tumor, stroke, or head injury.

Migraine

A migraine is not when you just have a headache. This is a severe pain syndrome that is not stopped by traditional analgesics. So, a cup of coffee, which in combination with NSAIDs usually relieves headaches perfectly, with migraines often leads to a sharp deterioration of the condition. Migraine affects about 20% of people in the world.

In 2019, the drug Irinex (erenumab) for the preventive treatment of migraine appeared on the world market, and since 2020 it has been registered in Russia. This drug is a human monoclonal antibody that selectively blocks the activity of the CGRP protein receptor (calcitonin-a gene-related peptide), which plays a key role in the formation of a migraine attack. Studies have shown that in patients receiving erenumab therapy, there was a significant decrease in the number of days with migraine attacks — in 50% by half, and in every fourth, seizures decreased after a year of therapy.

Of the advantages:

• The effect on one of the key mechanisms of migraine pathogenesis is the blocking of CGRP receptors.

• A single administration per month instead of daily long-term medication.

• There are fewer side effects, they are comparable to placebo.

Of the minuses:

Expensive, as is almost always the case with bioengineered drugs. The average cost of a dose of 70mg of erenumab (Irinex) in Russia is about 20,000 rubles.

Cholesterol metabolism

Many of you know that high cholesterol levels cause high risks of cardiovascular pathologies. Simply put, the chance of ischemic stroke, heart attack or other problems is higher. Thus, a meta-analysis based on ≈1,000,000 individuals showed an increase in the risk of cardiovascular diseases by 24% with an increase in cholesterol by 1 mmol/l.

A breakthrough has recently occurred in this area after the completion of clinical studies on PCSK9 — Repata (evolocumab) and Praluent (alirocumab) inhibitors. They not only effectively reduce the levels of low-density lipoproteins, but also have been proven to reduce the risks of serious cardiovascular events. Simply put, it is no longer necessary to die of a stroke at 35 if you are unlucky with genetics and cholesterol metabolism.

Based on research, the European Society of Cardiology has included these drugs in clinical guidelines.

Why is evidence-based medicine important?

The scientific method is not an ideal tool, but it is the best we have. A doctor who uses the tools of evidence-based medicine in his work:

He will not try to drip interferons into your nose and prescribe drugs that do not have proven effectiveness.

It will not perform aggressive surgical interventions where, according to research, therapeutic methods or minimally invasive endoscopic interventions can be dispensed with.

He is constantly studying and reading the latest clinical recommendations not only from Russian societies, but also from major international ones. Now more effective methods and drugs are constantly appearing. Treating a patient with 10-year-old methods is usually a bad idea.

Actually, that is why we value this approach in the treatment of patients so much. It gives you confidence that you are treating the patient as effectively as current technologies allow.

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