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.
“Synthesis usually starts with simpler molecules that do not have such a relatively complex-branched structure,” Niyazov explains. Favipiravir is obtained from the substances purchased by IIHR in three stages, the synthetic chemist says, according to his calculations, this volume should be enough for 460 courses or 33 thousand tablets. “But such purchases have risks. At the beginning of the synthesis of the intermediate, some conditions might not have been met and the reactions did not proceed under ideal conditions, which means that the product may contain impurities, ”Niyazov says.
Meanwhile, the sellers of the substance, who supplied the substance from China to Russian pharmaceutical companies, could not confirm to The Insider that they were producing the drug themselves, rather than purchasing it elsewhere. But they claim 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 usually “vague”, a researcher at one of the Russian pharmaceutical manufacturers (synthetic chemist) tells The Insider. 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. “It is impossible to develop a technology for industrial production quickly. During its creation, commissioning tests are carried out, not one or two experimental series, no one will use the tested technology, which exists only on paper, to obtain the drug, ”says Niyazov.
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. “With regard to drugs, no latent modifications are allowed. If they modified something, then what antiviral activity does this drug have? ” – says Niyazov. Vlasov also agrees with him: “If the drug is changed and reproduced not favipiravir, then this drug should go through a full cycle of clinical trials.”
The first study of favipiravir for efficacy against COVID-19 was registered in China in mid-February 2020. First results seemed quite encouraging: hospitalized patients got rid of the virus faster, and chest images 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 a placebo), and the drug did not show effectiveness… 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 turned out to be slightly better than the kaletra, however, in the article published as a result it saysthat since the sample of patients was small, and the study design is not entirely correct, it cannot be considered evidence of the efficacy 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 “Avivavir” in June 2020 simultaneously in 22 hospitals conducted Moscow State University professor Elena Pavlikova and Doctor of Medical Sciences Nikita Lomakin from the Central Clinical Hospital. In August 2020, they published results of a 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 rather random than a consequence of the manipulations carried out. 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 recommendation of the Ministry of Health.
“This drug was originally researched against common flu and showed very little effectiveness. Therefore, due to its toxicity, it was not allowed anywhere. Allowed only in Japan and then as a fallback. I Japan also conducted a study on its effectiveness against coronavirus. And this study also did not show great effectiveness. There have been studies of favipiravir in Russia, but they are all of very low quality. They were led by a certain urologist Dmitry Pushkar, why was it entrusted to the urologist? ” – the epidemiologist Vasily Vlasov is amazed. In May 2020, the chief urologist of the Ministry of Health of Russia Dmitry Pushkar told “Rossiyskaya Gazeta” that in Japan the drug “came to the court in the treatment of various viral infections, including the most difficult” – although in reality it was never used against diseases, but was only investigated for the treatment of influenza and the Ebola virus.
Japanese company Fujifilm Toyama Chemical developer back in September 2020 reported about the low effectiveness of 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. “The duration of the disease is twelve or fourteen days – for me the same … It turns out that for an amount of 20-25 thousand rubles, you pay for a reduction in treatment by two days. And at the same time, there is no data on a decrease in mortality: whether this drug decreases it or not, ”- spoke in an interview with Izvestia, Doctor of Biological Sciences, Professor, Corresponding Member of the Russian Academy of Sciences, Head of the Laboratory of Biotechnology and Virology of the Faculty of Natural Sciences of NSU Sergei Netesov.
The results of a clinical study of one of the largest pharmaceutical companies in Russia, JSC R-Pharm, were 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, the British academician 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 of 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, when researching in Japan, it was identifiedthat the use of the drug can lead to motor impairments in patients: the syndrome of night walking and fast running, 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 confirmed to The Insider 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 also issued in a mild form. [во время лечения на дому]”, – notes Vlasov.
A general practitioner from one of the Moscow polyclinics also confirmed to The Insider 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 Insider’s calculations, 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 for the amount of about 5 billion rubles. Most of the tenders were formalized as purchases from a single supplier.
The first packs of Avifavir on the market were sold to hospitals at 22,000 rubles for 40 tablets – a fantastically high price considering the purchase price of favipiravir in China (not to mention the fact that any price for an ineffective drug is too high). When Koronavir entered the market, 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 and in 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.