The virus of greed. "The main Russian medicine" for COVID-19 turned out to be a dummy purchased in China and extremely toxic
“Russia was the first in the world to register two drugs of direct antiviral action with proven efficacy to date,” the propagandist Dmitry Kiselev was delighted on the air of Vesti in July 2020. - And it is precisely against COVID-19 that these are the strongest ones to date, "Avifavir" from the company "ChemRar" and "Areplivir" from "Promomed". They prevent the multiplication of the virus in the body, and the effectiveness of these pills according to the results of clinical studies is 90%. So far, no other drug in the world has the best results against COVID-19. "
The truth in the words of the propagandist was only one thing: in the spring of 2020, the Ministry of Health really approved Avifavir, Areplivir and Coronavir for the treatment of coronavirus, and indeed, nowhere in the world were “antiviral” drugs against coronavirus used. These drugs are actually based on the active ingredient favipiravir , which was invented and patented in Japan in the early 2000s as a remedy for severe flu, and was also tested on patients with the Ebola virus, but in the end, favipiravir was never mass-produced. and in Japan itself was not used, since it was not possible to prove its effectiveness.
However, in mid-March 2020, Chinese officials suddenly announced the high efficacy of favipiravir against coronavirus. It was then that a number of large Russian companies - R-Pharm, Promomed, as well as ChemRar, with the support of the Russian Direct Investment Fund (RDIF), decided to launch the production of a Russian analogue. "In March, we heard the news that among hundreds of drugs tested in China, one showed breakthrough results, doubling the results of treatment," - this is how the chairman of the board of directors of ChemRar, Andrey Ivashchenko , described the start of work on the drug at one of the press conferences ...
In just a month, with the support of RDIF, a subsidiary of ChemRar, Kromis, not only recreated the drug, but on April 23 registered with the Ministry of Health the beginning of a clinical trial of Avifavir with 60 volunteers. Officially, it lasted until December 31, 2020, and the number of participants was expanded to 300 people. But in fact, no one expected the results of the study: already at the end of May 2020, the drug began to be used to treat patients.
The manufacturers at ChemRar explained such success by the fact that five years ago the company had already worked on a similar drug and synthesized the chemistry favipiravir. RDIF and ChemRar insisted that they were able to independently synthesize the active ingredient and test it for effectiveness in the shortest possible time. In May, the Russia-1 TV channel showed a story where it was said that it took ChemRar two weeks to synthesize the drug, and “not a single country in the world was able to buy either the drug itself or the raw materials for it”
Tons of substances from China
As The Insider found out, in reality, the drug "Avifavir" was of Chinese origin - Russian pharmaceutical companies simply bought "ingredients" on the Chinese market for a cheap price.
The editors have at their disposal the numbers of the declarations for the import of the substance. So, on April 2 and 6, and then on May 11 and June 18, almost 90 kg of substances came from a Chinese supplier to the production of the ChemRar company in Khimki, from which favipiravir can be obtained in several operations. The declared cost of the intermediates is only 23 million rubles, an insignificant amount in comparison with the billions in state procurement budgets. According to the Chinese seller, Jinlan Pharm-Drugs Technology Co., tens of thousands of tablets can be made from this amount - the correspondent spoke to him on the Alibaba marketplace, where the company's store was presented in 2020, and it was possible to buy the substance of favipiravir there. In 2021, it is no longer possible to buy this substance on Alibaba - at the request of the licensee, such goods were blocked.However, on the supplier's website, the link to the product is still available .
Other Russian companies acted similarly to ChemRar. Judging by the customs data, on May 30, 2020, R-Pharm's subsidiary company, Drugs Technology, received 5 barrels with 50 kg of ready-made favipiravir. The substance cost the company 48 million rubles. In total, as it turned out, since the beginning of 2020, the R-Pharm company imported into Russia almost 4 tons of the substance for the preparation of favipiravir tablets. This is evidenced by the data from the database of customs declarations Import Genius.
The fact that subsidiaries ChemRara and R-Pharm actually imported the drug substance was confirmed by The Insider by two independent sources in the pharmaceutical industry.
The substance purchased by Russian companies is an intermediate product that is obtained near the end of the synthesis of the final substance. This is the conclusion reached by Ravil Niyazov , a specialist in the development and regulation of drugs at the Scientific Consulting Center, and who wished to preserve the anonymity of a synthetic chemist of one of the Russian pharmaceutical manufacturers, who studied the declarations of R-Pharm and IIHR at the request of The Insider.
Meanwhile, the sellers of the substance, who supplied the substance from China to Russian pharmaceutical companies, could not confirm to the correspondent that they themselves produce this drug, and do not purchase it elsewhere. But they argue that the substances are in great demand among buyers from Russia, and from China they are supplied in “tons”.
Hazy patent and dangerous modifications
But could Russian companies really synthesize the substance on their own?
Theoretically, it is possible to reproduce an active substance molecule in a short time. In such cases, the patent of the original manufacturer is used, but the description of the synthesis in it is, as a rule, "vague", says a researcher at one of the Russian pharmaceutical manufacturers (synthetic chemist). Companies design patents specifically to protect their intellectual property.
Vasily Vlasov, a professor at the Higher School of Economics, President of the Society of Evidence-Based Medicine Specialists, believes that a substance can be synthesized in a month, but setting up an industrial synthesis can take months. Ravil Niyazov, a drug development and regulatory specialist at the Scientific Consulting Center, is of the same opinion.
Separate questions from the professional community are raised by the reports of the general director of "ChemRar" Ivashchenko that the company managed to modify the drug.
Volunteer research
The first study of favipiravir for efficacy against COVID-19 was registered in China in mid-February 2020. The first results seemed quite encouraging: hospitalized patients cleared the virus faster, and chest scans showed positive dynamics. The study with the largest sample of patients was also held in China at the end of February. In it, favipiravir was compared with arbidol (as with placebo), and the drug was not shown to be effective . The study involved 240 people.
At the same time, a comparison of the effectiveness of favipiravir with kaletra, an HIV drug that has also been tried around the world for the new coronavirus, began. 80 people were selected for the study. The results of favipiravir were slightly better than kaletra, but the final article stated that since the sample of patients was small and the study design was not entirely correct, it cannot be considered evidence of the effectiveness of favipiravir, and more research is required. However, it is this article that the Russian Ministry of Health refers to, explaining why it chose favipiravir as the recommended medicine. An article with the results of the study was published on March 18, and exactly on the same day, the Chinese regulator rushed to announce the effectiveness of the Chinese medicine against the new virus.
In the UK, France, the United States, the Middle East and South Asia, studies have been conducted on the efficacy of favipiravir. However, first, they investigated the original Japanese drug, which is produced under the Avigan brand or Indian licensed generics. Second, while some of these studies have shown the drug to be effective when compared to other antiviral drugs (such as remdesivir), it was a mild to moderate coronavirus, so even if these results could be trusted, they are still irrelevant - the drug is very toxic, and therefore it still cannot be used to treat mild forms of coronavirus.
In the world's largest database of clinical trials of drugs, ClinicalTrials, there is information that the study of Avifavir in June 2020 was simultaneously conducted in 22 hospitals byMoscow State University professor Elena Pavlikova and Doctor of Medical Sciences Nikita Lomakin from the Central Clinical Hospital. In August 2020, they published the results of the study in the journal Clinical Infectious Diseases.
However, it turned out that the study was sponsored by RDIF and the Skolkovo innovation center, the resident of which is the drug manufacturer, Khimrar. A total of 60 people participated in the study, 40 of whom received avifavir and other drugs (which are not specified), and 20 - various antiviral drugs, mainly hydroxychloroquine, along with antibiotics and antipyretic drugs. Two people with more severe illness died during the study. The authors conclude that Avifavir works better than standard therapy, although after 10 days of treatment, the p-test (the level of significance of the results that determines how statistically significant the outcome of the experiment is) was 0.155. The higher this indicator, the more likely it is that the result obtained is more likely random,what is the result of the performed manipulations. In medicine, it is usually used as a threshold p-criterion not more than 0.05, sometimes 0.01, that is, Russian researchers deviated by an order of magnitude from the standard requirements. The authors of the study emphasize that it was these clinical trials on 60 volunteers that caused the drug to be included in the recommendations of the Ministry of Health.
In May 2020, the chief urologist of the Russian Ministry of Health, Dmitry Pushkar, toldRossiyskaya Gazeta that in Japan the drug “came to the court in the treatment of various viral infections, including the most complex ones,” although in reality it was never used against diseases, but was only studied for treatment for influenza and Ebola virus.
Back in September 2020, the Japanese company developer Fujifilm Toyama Chemical reported low rates of effectiveness of the substance favipiravir - according to their study, those who took the drug were discharged from the hospital after 12 days, those who were given a placebo - after 15. “Duration of the disease that twelve, that fourteen days is the same for me.
It turns out that you pay 20-25 thousand rubles for a two-day reduction in treatment. And at the same time, there is no data on a decrease in mortality: whether this drug reduces it or not, " Sergei Netesov , Doctor of Biological Sciences, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Biotechnology and Virology at the Faculty of Natural Sciences of NSU , said in an interview with Izvestia .
The results of a clinical study of one of the largest pharmaceutical companies in Russia, JSC "R-Pharm" have been published in September 2020 in the Russian journal Medical Opponent. Olga Filon, Medical Director of Tekhnologiya Medicinskii LLC, participated in the study, and the study was funded by R-Pharm. The trials also involved 60 people, 40 of whom received favipiravir, and another 20 received other drugs that the authors did not disclose. In addition, almost all patients received antibiotics, anticoagulants and antipyretics, that is, the standard therapy approved by the Ministry of Health. Unlike the Khimrar study, experts did not recruit seriously ill patients to the trial, and not a single patient died. The time of destruction of the virus in the body of patients receiving favipiravir practically did not differ from the rest of the patients; the patients' condition improved 3.5 days earlier.
The practice in which pharmaceutical companies finance clinical trials of their own drugs is considered questionable in the scientific community. For example, British author Ben Goldacr, in his book Bad Pharma: How Drug Companies Mislead Doctors and Harm Patients, provides statistics that most often such studies are complementary, and studies in which the effectiveness the drug has not been proven, just not published. In addition, studies are often poorly designed, conducted on a small number of subjects (as happened, for example, in the case of Russian generics of favipiravir), and the results may be skewed in favor of a particular drug.
More Poison Than Medicine
While the efficacy of favipiravir is highly questionable, its dangerous side effects, on the other hand, are well established. Due to its toxicity, the drug is prohibited for children, pregnant women, lactating women, as well as people with severe hepatic or renal impairment. Due to the high likelihood of a negative effect on the fetus, people who have taken the drug are recommended to pay special attention to contraception for several months. Also, in a study in Japan, it was found that the use of the drug can lead to motor disorders in patients: restless legs syndrome, as well as an increased risk of falls. Experts believe this may be due to the drug's effects on the central nervous system.
Drugs with such high toxicity are usually used only in cases when their effectiveness is high and the patient is in serious condition, that is, the risks from the disease outweigh the risks from the use of the drug. In addition, toxic drugs are used only in hospitals under the strict supervision of doctors. In the case of Russian generics of favipiravir, all these requirements were violated.
Several employees of Moscow hospitals specializing in the treatment of coronavirus have confirmed that drugs based on favipiravir (Coronavir and Avifavir) are regularly given to patients and are included in treatment plans for seriously ill patients. “Initially, pharmaceutical companies registered their Russian counterparts as a medicine against severe cases of the disease, which, due to its toxicity, should be used in hospitals. But in practice, it is given out even in a mild form [during treatment at home], ”notes Vlasov.
A general practitioner at one of the Moscow polyclinics also confirmed that all confirmed cases of Covid-19 are now being treated with Russian generics of favipiravir even at home in Moscow.
Money is not contagious
Mass deliveries of Avifavir to the regions of the country began in June 2020 and have been increasing since then. According to the calculations of the editors based on data from the public procurement portal, by August 1, 2021, the authorities had purchased Russian generic drugs for at least 10 billion rubles. Only the R-Pharm company directly delivered the drug to the hospitals in the amount of about 5 billion rubles. Most of the tenders were formalized as purchases from a single supplier.
The first packs of Avifavir to hit the market were sold to hospitals at 22,000 rubles for 40 tablets - a fantastically high price given the purchase price of favipiravir in China (not to mention the fact that any price for an ineffective drug is too high). When Coronavir entered the market, its price for different hospitals ranged from 3 to 5 thousand rubles for a pack of 50 tablets. In the fall of 2020, the drug was released for retail sale, in pharmacies it costs around 5 thousand rubles per pack. At the same time, in the homeland of the drug in Japan, its retail sale is strictly prohibited and only hospital use is allowed.