Principles of drug development
Evidence-based medicine
Yaroslav Ashikhmin, Post-scienceBut is it possible?
– to raise the question of the right of a doctor to treat? If you think this way, if you doubt every method that is scientifically accepted today, whether it will not be discredited or rejected later, then you can get to the devil knows what! After all, deaths are described even from aspirin: a person took his first aspirin in his life and died!.. Then it is impossible to treat at all! Then it is impossible to bring everyday benefits at all.
Alexander Solzhenitsyn. "Cancer Corps"
Evidence–based medicine is a new concept of medicine, which is based on the fact that making specific decisions regarding the treatment of a patient should be based on clear evidence of the effectiveness and safety of existing treatment methods obtained during clinical trials. Today, evidence–based medicine serves as a motor for improving clinical practice, in the West it has been introduced into all areas of medical activity - from the principles of communication with patients to diagnostic strategies and treatment proper.
One of the founders of evidence-based medicine was Professor Archie Cochrane, who in the middle of the XX century thought about how effective the methods of treating infectious diseases known at that time were in reality. The fact is that when we give a patient some medicine and he gets better, it is not always related to the effect of the medicine per se. In about a third of cases, its effect is determined by the "miraculous" power of the placebo. Placebo, by the way, has always been widely used in medicine. So, the great therapist Mudrov used "gold", "silver" and "simple" powders – although containing chalk, but very effective. In fact, one of the modern types of placebo therapy is homeopathy. To date, the effectiveness of homeopathic medicines has not been proven in any placebo-controlled randomized trial. The researcher who will be able to scientifically prove its effectiveness by the James Randy Foundation will be awarded a $1 million prize.
But of course, drugs that have been tested in the course of serious research work much more effectively.
The methodology of evidence-based medicine is based on conducting clinical trials that are based on a specific design. One of the key principles of evidence-based medicine is the "double-blind method". The patient signs an informed consent stating that he can receive either a drug or a placebo, and the attending physician also does not know into which group each of the patients included in this study will be randomized. At the same time, in fact, the placebo is often not a "dummy", but a generally accepted method of treatment, with which a new one is compared. The Ethics Committee will never allow the use of a real "empty" placebo in the case when the treatment of the disease has already been developed.
The cards are opened only after the patients in both groups have completed a full course of treatment. At the next stage, statistical processing takes place. And only by applying clear statistical criteria and analyzing a large number of observations can it be proved that the new drug is effective. Interestingly, the Student's criterion, widely used to determine whether a medicine works, was invented by William Grosset, who took care of how not to overdo it with yeast at the famous Guinness brewery. Another criterion was proposed by Fischer, who thought about how many cups of tea with milk should be tested to find out if a lady who assures him in a small talk that she knows how to distinguish whether milk or tea is poured into the cup first is deceiving him. What would these mathematicians think if they found out that their criteria would later be used in solving life and death issues?
The methodology of evidence-based medicine is often criticized from a variety of positions, but we do not have any other tool to assess the actual effectiveness and safety of treatment.
And now let's look at the situation from the point of view of a person who came to the pharmacy for an over-the-counter drug. How can he distinguish between drugs that have passed such clinical trials? The following should be taken into account here.
Today, pharmacology goes in two ways: the first way is the release of so–called biologically active additives that do not pass clinical trials, and, as a rule, most of them do not work. As a practicing doctor, it is difficult for me to answer why they are in the pharmacy. A concrete example is multivitamins created for good purposes. One of the central dogmas of modern medicine is that if something very important is missing in the body and you bring it from the outside, it can not always increase the level of health.
A lot of studies that have been published in the most authoritative journals (such as Circulation, New England Journal Of Medicine, etc.) have shown that long-term use of multivitamins not only does not lead to an improvement in the prognosis for life, but is probably also associated with an increased risk of heart attacks and certain types of cancer (in particular, lung cancer). But people, for reasons that many doctors do not understand, continue to buy them. Here another periodox medicine manifests itself – if you subjectively feel better "from the medicine" (as from multivitamins – "fresh"), this does not mean at all that the medicine really improves some parameters in the body and, moreover, that you will eventually prevent the development of the disease.
And the second path is the production by large pharmaceutical companies of medicines developed by serious scientific teams. They are licensed at different levels and undergo serious clinical trials. Your doctor should know which of them can be trusted: data on the actual effectiveness of almost every "pill" can be found in specialized medical search engines.
So, when you come to the pharmacy, you see a lot of drugs, and it may seem to you that they can cure most diseases. Interestingly, in fact, not so many really effective medicines have been created recently. In order for an effective drug to be developed, there must be a combination of several factors:
- social significance of the disease;
- known molecular mechanisms of its development;
- material possibilities for the creation of a drug, including suitable biological models and synthesis techniques that can be used on an industrial scale.
It should be understood that even a very effective drug will not be promoted if it does not find a convenient dosage form. Apo A1 Milano is a peptide drug, only a few intravenous injections of which can significantly reduce the size of atherosclerotic plaques in the coronary arteries (according to high–precision intravascular ultrasound). A similar effect can be achieved by taking standard lipid-lowering drugs for many years and in high doses. This medicine probably does not enter the market not only because of the high cost, but also because of the lack of opportunity to make a form for per os application. Other striking examples are immunoliposomes and dendritic cell vaccines against tumor antigens, which are extremely difficult to manufacture or use in practice.
There are several concepts for creating medicines. The first is the development of so–called individualized or personalized treatment. Let's consider this process on the most striking example of orphan drugs, exclusive remedies for the treatment of a number of rare diseases. They begin to be created, either when a scientist suddenly realizes that a biochemical or genetic defect associated with the disease is simply enough to compensate, or when the suffering of a small group of patients is too strong, which encourages their relatives or sympathizers to invest in the development of treatment funds that are unlikely to ever pay dividends, but will save lives. After that, a group of researchers gathers, and they develop a targeted drug that hits exactly one single target. As a rule, this is either the synthesis of a substance that replaces something missing in the body of a sick person, or the creation of a molecule that interacts with the affected receptor that determines the course of the disease. If the disease is realized through many mechanisms, as in the case of, for example, heart disease, it is almost impossible to come up with an orphan medicine.
After determining the target, the search for those compounds that bind to the necessary receptor takes place, or a molecule is developed that replaces something missing in the body, and a system for its delivery. Some of these processes are simulated on a computer, then chemists carry out directed synthesis, and after that, the affinity of the molecule to the receptor of interest to us is tested on certain models. Then it is determined whether it can work at the cellular level and on biological models (which are usually rodents). The effect of the use of orphan drugs can be seen quickly enough. We can consider this by the example of hereditary diseases of babies associated with a lack of certain enzymes in the liver. If we give such a drug to a child who would have died without it in 100% of cases, and the baby survives, this is an absolute proof of effectiveness. Such drugs are also created for the treatment of rare cancers, blood diseases and multiple sclerosis.
The situation is fundamentally different in the treatment of chronic diseases, such as hypertension, heart failure, diabetes mellitus, chronic obstructive pulmonary disease. Such funds have been accepted for decades, and their impact on mortality is quite difficult to track. The main difficulty lies in the fact that when a researcher holds in his hands a molecule that works perfectly on some model and even in several patients, it is extremely difficult to understand whether it will work in 10 years on another patient population. And when scientists study this molecule, which, for example, lowers blood glucose levels in diabetic patients, they are usually interested in getting funding to continue their research.
Another threat lies in the species-specificity of drugs. Recently, many molecules have been created that "work" only in rodents, but not in rabbits, pigs and dogs. Obtaining funds to continue their research, knowing that the drug will not be effective in treating people, leads medical science to a dead end.
Trying to discover something really new is a big risk for the research team, because if it fails, it can literally fly out of the academic cage. This is how science is becoming opportunistic today. If a researcher in America suddenly realizes that he can do differently, can make a molecule that will work, act on another link in the molecular cascade, then he is often besieged, because he must work clearly in the rut in which the laboratory has been working for many years. Priority is often given to the work of knocking out grants, without which the team simply will not survive. And if the laboratory goes beyond its field of research, which is usually very narrow, then the grant may not be allocated. That is why innovative ideas often die.
The molecules developed and shown to be effective "in vitro" enter preclinical trials, then pass the first phase, in particular, on healthy volunteers. Original molecules are usually developed by small teams of researchers, but the rights to them belong not to scientists and doctors, but to completely different persons, for whom the main goal is often to sell a promising molecule to a large pharmaceutical company as expensive as possible. Even in the West, the academic circle is very narrow, so the advantages of the molecule can be embellished and seasoned with positive reviews, and therefore large companies risk buying a "pig in a poke". An unsuccessful drug is sure to "fail" at the crucial, third, phase of clinical trials, which are conducted on thousands of patients and are led by indisputable leaders of scientific opinion. So, a drug that perfectly reduces glucose in the blood may not prevent the development of fatal complications of diabetes mellitus in comparison with metoformin used since the middle of the XX century. In the last few years, a large number of "innovative" drugs, which are found in abundance on pharmacy shelves, have not shown statistically significant superiority over placebo or traditional treatment in clinical studies.
The inclusion of the principles of evidence-based medicine in the backbone of clinical research protocols has dramatically increased the safety of medicines in the long term. As an illustration, antiarrhythmic drugs of the Ic group can be cited. These remedies are perfectly tolerated by patients and remove the most severe rhythm disturbances. The quality of life of patients taking these drugs is improving. Therefore, sudden deaths of patients taking class Ic antiarrhythmics were associated by doctors with arrhythmia, for which patients received treatment. And until the completion of major studies, it seemed that these funds were ideal. But statistical analysis showed a sharp increase in mortality associated with prolonged use of the studied antiarrhythmic drugs in certain categories of patients. No other method, other than a blind scientific one, would make it possible to determine the cause of sudden death of patients who receive symptomatic relief from treatment.
As for the "dangerous" antiarrhythmics, they were not discounted, but studied more deeply and subsequently found situations where these drugs can be useful and safe (in particular, with cardioversion).
Evidence-based medicine today is opposed to such an approach as talented medical care, that is, precisely selected, individualized treatment "not according to recommendations". In some studies, it has been shown that in some rare diseases, patients receiving talented medical care live slightly longer than those who received therapy strictly according to clinical recommendations. In our reality, this approach can be extremely dangerous due to the fact that today in Russia only a few specialists have the appropriate level of knowledge and experience to conduct talented medical care. Unfortunately, the treatment that is widespread today based on "many years of own experience" has nothing to do with individualized treatment. No matter how highly qualified a doctor is, he faces a certain contingent of patients and hones a limited set of methods. Even having a very good knowledge of the treatment method A, the doctor should critically review the treatment strategy after the publication of data from a large study, which clearly shows that the method B is significantly superior to A in effectiveness and safety.
Today, some of the most sought–after specialists in the field of drug development are those who are engaged in the so-called translational medicine, that is, people who, after seeing the very first phases of trials, can predict the fate of a drug and offer new experiments to clarify the balance of risks and benefits (if possible, without involving patients!). But there are very few such specialists, especially unbiased ones. It is precisely because of the mistakes of specialists in translational medicine or because they simply were not involved, it is often only at the final third phase of clinical trials that it turns out that the drug that showed excellent results in the first stages does not work in reality. A pharmaceutical company, having spent many years and tens of millions of dollars on research, only at the last turn understands that the drug cannot be used. And that is why those drugs that were finally brought to the market are so expensive - due to their sales, it is necessary to cover the losses of the "casino for the creation of new molecules".
One of the most important aspects here is, of course, the issue of humanism: when developing new drugs, researchers should "keep in mind" the clinical picture of a particular disease or images of people suffering from it. And in the case of socially significant diseases, already at the first stages of creation, think about how to make treatment available to a wide range of the population.
The question of how to harmonize this system and make an effective medicine more accessible is extremely difficult. The first is the search for new approaches and new molecular "targets". But the problem is that new highly efficient molecules are often created by small teams, and it is extremely difficult to understand which of them really deserves attention: there are too many crooks. Finally, there are very few experts in the world today who can separate the wheat from the chaff. The search among these small teams for those who produce a truly innovative, effective product is now a key, fundamental task. It is important not to be deceived at the very beginning of the journey.
Literature:
- http://en.wikipedia.org/wiki/Translational_medicine
- http://www.cochrane.org/
- Finniss D.G., Kaptchuk T.J., Miller F., Benedetti F. Biological, clinical, and ethical advances of placebo effects. Lancet. 2010; 375: 686–695.
- Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS (January 1996). «Evidence based medicine: what it is and what it isn’t». BMJ 312 (7023): 71–2.
- http://trv-science.ru/2012/10/09/recepty-iz-povarennojj-knigi-klinicheskikh-issledovanijj/
The author is a candidate of medical sciences, a practicing cardiologist.
Portal "Eternal youth" http://vechnayamolodost.ru14.05.2013