After the recent debate, Anatoly Chubais and I agreed to continue the discussion about the drug Kagocel, which is being presented as the “crown jewel” of RUSNANO’s achievements.
As promised, Anatoly Borisovich published a list of studies and publications concerning the drug. That publication did not satisfy us in the slightest (or many others, for that matter).
The ACF has no doctors, biologists, or pharmacists on staff, but there are many experts whose knowledge and objectivity we have no reason to doubt.
We asked the well-known physician, Candidate of Medical Sciences, internist, cardiologist, healthcare administrator, member of the American Heart Association and the European Society of Cardiology, and author of more than 85 scientific publications, Yaroslav Ashikhmin, to prepare a response article to the head of RUSNANO.
Yaroslav kindly agreed and wrote the text in a popular science style so that it would be understandable to a broad audience.
Below is the full text, followed by some of my own thoughts on how this discussion may develop further.
The drug Kagocel belongs to the group of so-called “immunomodulators” and “interferon inducers,” which are supposed to strengthen the immune response against viral infection. In a test tube, that is indeed what happens, but the human body is far more complex. Imagine that the immune system is an army and the virus is an aggressor. The appearance of a virus in the body triggers a powerful activation of the immune system and naturally boosts the synthesis of protective interferon almost to its maximum. Now imagine that while the army is deploying its forces, aliens suddenly appear out of nowhere and club every soldier over the head indiscriminately in order to “stimulate them for battle” even more. That is roughly what happens when “immunomodulators” enter the bloodstream. It is important to understand that humans have coexisted with viruses since they first appeared on Earth. The immune system is superbly fine-tuned; it can be compared to elite special forces units (the notorious idea of “reduced immunity” is one of the myths successfully exploited by manufacturers of immune stimulants).
In most cases, adding an “immunomodulator” has no effect whatsoever on the course of the war against the virus: professional soldiers ignore a light blow from a club and keep doing their job. Viruses do acquire partial “resistance” to interferons, but the immune system has many other special tools in its arsenal, many of which, incidentally, are dramatically more effective than the “interferon system.” There are other scenarios as well. If, because of individual characteristics of the body and the type of virus, interferon works extremely well, the army may fail to develop an effective plan for repelling a new wave of infection (specific immunity will not fully form). And instead of neutralizing a similar virus very quickly the next time it appears, it will wait for outside stimulation (meaning you will go buy an immune stimulant—which is exactly what the manufacturer hopes for). The second scenario is much worse. In every person’s body, cells with mutations of varying degrees of danger appear from time to time. These may be isolated deserters, quickly detected and destroyed by the immune system’s own “internal security unit,” or they may be an entire “underground network” not yet identified by it (blood cells with precancerous changes). An immunomodulator taken with good intentions may give these saboteurs additional strength (stimulate a clone of cells that has embarked on the path of malignant transformation), and a few years later they will “emerge from hiding”: hemoblastosis, or “blood cancer,” will develop. As long as there is even a small possibility of such an outcome—that is, as long as the long-term effects of interferon inducers and immunomodulators remain unknown—they should not be used on a mass scale, especially in children, whose immune systems are still developing.
And no trustworthy clinical trials of Kagocel have been conducted. Meanwhile, the drug has not only been registered and widely used—it has been added to the List of Vital and Essential Medicines (Russia’s official list of critically important drugs), which automatically opened the door to the government procurement market. The joke that “you simply can’t survive without Kagocel” will not seem funny to thousands of our fellow citizens who are dying because truly life-saving medicines are unavailable—because those medicines were not included on the list, which means it is practically impossible for clinics to purchase them.
All of the English-language articles (including those cited in Anatoly Chubais’s post) are not clinical trials. They are literature reviews on immunomodulators and studies of Kagocel conducted on cell cultures and laboratory animals. They cover only the very earliest stage of drug development. The entire history of pharmacology shows that blindly extrapolating such results to humans can lead to all kinds of complications.
It is very important to understand that the potential market for antiviral drugs amounts to many tens of billions of dollars, because viral infections are extremely common. If investors had even minimal confidence that a drug was at least somewhat effective, they would immediately fund a high-quality clinical trial and publish it in a respectable journal, opening access to the global market. Look at the situation with the acute respiratory viral illness caused by the new coronavirus—MERS. How much do you think South Koreans would be willing to pay for a package of a new effective antiviral drug? Why is it that they still know nothing about these miraculous “interferon inducers” and immunomodulators, which by that logic ought to be effective against all acute respiratory viral infections, including the coronavirus that causes MERS?
The strategy is simple: if the drug is selling (in Russia, to the tune of 2.5 billion rubles a year!) then there is no need to study it any further. Unfortunately, sales volume is far from reliable proof of a medicine’s effectiveness or quality.
During the debate, Anatoly Chubais mentioned the FDA, which approves drugs for use in the United States. Try finding even a single mention of Kagocel on the FDA website or in the international clinical trials database ClinicalTrials. In reputable scientific journals, including Russian ones, indexed by the world’s largest scientific library, PubMed, the results of not a single (!) randomized clinical trial of Kagocel have been published. You do not need to be a pharmacist to understand from the article titles that the studies were conducted on rodents and cell cultures.
Anatoly Chubais is playing a shell game with us. He writes that “about 2,000 patients in total took part in the registration clinical trials,” and then brandishes the figure of 21,000 people who supposedly participated in a “post-registration study.”
To understand where Anatoly Chubais is being misleading, and why the clinical studies listed in the bibliography cannot be considered sound, one needs a certain level of basic training. In short, modern medicine accepts only one particular type of study as evidence of effectiveness: the so-called double-blind, placebo-controlled trial. Such studies are conducted according to a very strict protocol and must include a precise description of the patient groups being compared, the criteria used to assess efficacy and safety, the statistical methods applied to the data, and detailed results. (A popular explanation of clinical trials, as well as the power of the placebo effect—which must always be accounted for—can be found here)
Most of the materials Chubais mentions are simply literature reviews, low-quality non-randomized studies, or even outright propaganda pieces. You do not have to be a statistician to see that, do you? There are a few randomized clinical studies, but among this entire pile of materials, not a single one meets strict evidentiary standards.
The “strongest” papers in the dossier are this one and this one, but even these were conducted as single-blind studies—that is, the researchers knew who was receiving Kagocel and who was receiving placebo, which could have affected the results. The first study included only 81 people, and the second, 60 children. Surely you will agree that this is nowhere near “2,000 patients.” The papers say nothing about the statistical methods used, nor do they provide the baseline characteristics of the patient populations on the basis of which their comparability was supposedly established. The flaws are so serious that no self-respecting medical journal, Western or Russian, accepted these studies. That is why they were all published in “second-tier” journals that may not even have a scientific editor or peer reviewers.
As for the post-registration study involving 21,000 people, it was an observational, “non-interventional” study—that is, it was not fundamentally designed to investigate the specific drug Kagocel, as is honestly stated, incidentally, in the study table cited by Anatoly Chubais. The figure 21,000 sounds impressive, but behind it—put delicately—there is nothing.
This list is very interesting in itself.
For example, it shows that not a single Phase III trial was conducted in adults (without which registration is formally impossible), and not a single Phase II trial was conducted in children (even though such trials are necessary to assess safety and determine dosage).
Nowhere can one find the results of the key Phase II studies it mentions on the treatment and prevention of influenza, involving 262 and 719 adult patients with influenza and acute respiratory viral infections. Most likely, they were never published at all.
Incidentally, all the main reviews of Kagocel studies cite a study that has never been published anywhere (!), conducted “at the Research Institute of Influenza of the Russian Academy of Medical Sciences, the D.I. Ivanovsky Research Institute of Virology of the Russian Academy of Medical Sciences, and the S.M. Kirov Military Medical Academy during the period 2000–2003,” in which exactly 550 patients were assigned to each of the Kagocel and placebo groups.
You do not need to be a specialist to see that the materials provided by Anatoly Chubais contain no references to most of the studies from the “registration” dossier. The articles posted on the Kagocel website were written by entirely different authors. Mr. Chubais, how exactly are we supposed to review all of these studies? Incidentally, we would also very much like to see the results of the pharmacoeconomic studies, without which the drug formally cannot be included in the List of Vital and Essential Medicines. And the materials that were submitted to the FDA.
Unfortunately, the situation with Kagocel—where a drug that has not undergone proper testing is not only brought to market but also added to the List of Vital and Essential Medicines—is not unique in modern Russia. The domestic pharmaceutical business is governed by utterly lawless practices. Other well-known “antiviral” drugs—Amiksin, Anaferon, Arbidol, Ingavirin, Viferon, and so on—are no better than Kagocel, and some of them have been studied even less and may well be even more dangerous.
Most importantly, I find it hard to understand how RUSNANO decided to invest in Kagocel at all. If you want to run an honest business, then investing in drugs like Kagocel is, at the very least, foolish. It is roughly like developing the perfect club while fighter jets are roaring overhead. Interferon induction and nonspecific (“massive”) immune stimulation are archaic approaches that the West has largely abandoned. The prevailing view is that one should not meddle with the exquisitely fine-tuned immune system using an adjustable wrench. What the body’s defenses need is the most favorable possible environment—rest, plenty of fluids, and proper nutrition. Then the body will not only cope with the infection on its own, but will also “learn” to repel new viral attacks more quickly. The main direction of pharmacological development is the creation of vaccines and drugs that target the virus directly; the next step is ultra-precise influence on individual links in the immune system, which are only just beginning to be discovered.
And RUSNANO should not be surprised that, of all its controversial projects, Kagocel is the one for which it will have to answer separately. Because, as a famous character from Soviet cinema once said, “That’s gasoline, but these are children” (i.e., some things are in a completely different moral category).
Article by Yaroslav Ashikhmin.
Many thanks to Yaroslav for the article and for his help in analyzing RUSNANO’s biomedical projects.
What should be done next? This is an important question, and it concerns not only the dispute around RUSNANO but the medical field in general—a drug facing such serious objections cannot remain on the list of vital medicines.
I see two steps:
Publication of all study materials mentioned by RUSNANO for independent analysis. First and foremost, this concerns:
A) A multicenter randomized placebo-controlled study evaluating the efficacy and safety of Kagocel for the treatment of influenza and other acute respiratory illnesses in adults (2001, 262 patients enrolled) B) A multicenter randomized placebo-controlled study evaluating the efficacy and safety of Kagocel for the nonspecific prevention of influenza and other acute respiratory illnesses in adults during a period of mass seasonal incidence (2001, 719 patients enrolled) C) A multicenter blinded randomized placebo-controlled study evaluating the efficacy and safety of Kagocel for the treatment of influenza and other acute respiratory illnesses in children aged 6 to 17 (2007, 120 children) D) A multicenter blinded randomized placebo-controlled study evaluating the efficacy and safety of Kagocel for the prevention of influenza and other acute respiratory illnesses in children (2008, 180 children)
The creation of an independent expert commission (one whose independence would be recognized by people such as Ashikhmin or Okhotin—critics of Kagocel) that would conduct a special open review of all studies and publications concerning this “miracle drug,” document the results of its work, and publish them in full.
If RUSNANO is interested in ensuring that its biomedical projects are not called into question, then these two simple steps are in its interest as well.