The effectiveness of favipiravir is in question – yet those in Hungary who have expressed concerns have been prosecuted

• Hungary's National Institute of Pharmacy and Nutrition (NIPN) has filed criminal charges over newspaper articles questioning the effectiveness of favipiravir. It has not yet been revealed what exactly the authorities are concerned about, nor have they said on what basis they consider the drug, which has been widely used in Hungary, to be exempted from criticism. The little that has been said is not very convincing.
• The scientific findings on favipiravir are mixed, and to date there is no really strong evidence that it has been effective against Covid-19. But neither is there any clear indication to the contrary. Indeed, efficacy is not an absolute concept suspended in a vacuum: the usefulness of a medication depends largely on when, how and in place of what alternatives it is administered.
• According to the head of favipiravir's development in Hungary, the drug can be beneficial if used properly, but there are much better alternatives available today, and we should be shifting towards them. And this is already starting to happen.
• One thing is certain however: a police report is not a solution to a scientific debate. This move by the NIPN has been met with outrage and bewilderment in the scientific community.

The National Institute of Pharmacy and Nutrition announced on January 31 2022 that it is filing charges for scaremongering in connection with several newspaper articles questioning the efficacy of favipiravir against Covid-19. According to the NIPN, these articles can undermine the fight against the pandemic by eroding trust in medicines. The move has provoked a backlash, as it is unprecedented for a public body to respond to statements by respected scientists with criminal charges.

Although the NIPN did not specify which articles it was referring to, based on the news of the pandemic, it is not difficult to speculate that it is related to the articles on 24.hu and Qubit. We asked the pharmaceutical authority whether these were the articles they had in mind, but it was not clear from their reply. Nor did they clarify which claims they objected to or on the basis of what evidence.

This article outlines favipiravir's track record in Hungary, what the debate surrounding the drug is about, what is known about its effectiveness and why the whole issue might soon be put to rest.

Favipiravir's journey in Hungary

Favipiravir itself was originally developed in Japan to treat influenza, where it was licensed in 2014 under the brand name Avigan, but is also produced as a generic medicine in several other countries. Given that there were obviously no medications designed to fight Covid-19 at the start of the pandemic, researchers began to assess what existing compounds could be used to treat it. Many of the drugs tested were found to be ineffective early on, however others had shown promising results only to later prove unsuitable. Yet some compounds still seem to have a potential role in the treatment of covid patients.

Favipiravir – which we already reported on in detail in an article in March 2021 – is an antiviral drug that is being tested for use against the Ebola and Nipah virus, as well as influenza. The key to its mode of action is that it interferes with the replication process of the virus and introduces errors, effectively sabotaging the virus's ability to multiply. The aim is to reduce the viral load, prevent the disease from worsening and speed up recovery, thereby relieving the burden on hospitals.

According to Hungary's Covid treatment recommendation, the drug is indicated for mild to moderate patients in the early phase of the disease, within 3-5 days after the onset of symptoms (for mild patients it can be prescribed in primary care, i.e. at the discretion of a primary care doctor, and for moderate patients it is recommended in outpatient care). It can be obtained free of charge from pharmacies by prescription.

Most of the side effects are mild – although photosensitivity and the associated possibility of fluorescent nails, eyes and hair are still being investigated – but there is one known, serious risk: it can be harmful to fetuses, so it should not be taken by women who are pregnant, breastfeeding or planning to have children, or by men who are involved in the latter. That is why they make everyone who takes it sign a waiver.

At the start of the pandemic, there was little scientific evidence (beyond anecdotal medical reports) that favipiravir could be of use against the coronavirus: in particular, China, Russia, and Japan had each published one study. But many countries have tried to make use of all the resources they can to fight the pandemic. And so did the Hungarian government: in April 2020, it had already purchased 400,000 tablets of favipiravir from China, and since it can be freely manufactured, domestic development also began. In May 2020, it was announced that the first phase of this was completed. Meanwhile, 12,200 doses arrived from Japan for testing at the end of that month.

The NIPN authorized its use in early October 2020 in a clinical trial involving several hospitals (although, as we will see, only one clinical trial has been published, and that was with patients who had been treated earlier). By November 2020, millions of tablets were already arriving from China and Japan.

In early December 2020, favipiravir was incorporated into the national treatment guidelines and by the end of the month it was made available in outpatient care. At this time, the NIPN also authorized the development of two domestic versions of the medicine: Egis and Meditop. And since January 2021 Hungary has been mainly using these domestically-produced tablets. For the 2.8 million Chinese and 2 million Japanese doses that had been received up until that time Hungary paid a total of HUF 1.76 billion.

Given that antiviral medications are most likely to be effective in the first, viral phase of the disease, favipiravir had the great advantage of being administrable in tablet form, unlike, for example, remdesivir given to critically ill patients, and therefore did not require hospitalization. As such, it represented a huge leap forward, and at the time many experts welcomed the move to allow primary care doctors to prescribe favipiravir starting from the beginning of March 2021, as well as doctors working in Covid outpatient clinics and on-call doctors working nights and weekends.

Meanwhile, back in Japan, where the drug had been developed, the Ministry of Health stopped a clinical trial of favipiravir that had been running since early 2020, and since then the drug has not been given to any more covid patients. Nor do the US, UK or German treatment recommendations include favipiravir, nor do the World Health Organisation (WHO) guidelines, and Australia's recommendation explicitly does not recommend its use.

At the same time, it can't be said that favipiravir is not being used anywhere: apart from China, India, Russia and Turkey, it is also available in neighboring Serbia and Romania, where Hungary sent a thousand boxes of it in the fall of 2021 as aid during the fourth wave. Russia is also producing its own version of the drug, and the UK has been testing it since the spring of 2021 on individuals who don't require hospital treatment as part of the PRINCIPLE trial.

The NIPN refuses to specify what the problem is

Since the NIPN has been accusing the researchers quoted in the news articles of scaremongering, it is worth considering the scientific evidence behind their position – or rather, it would be worthwhile, but the institute hasn't presented any. "In the Authority's view – after taking into account the opinion of the Association of Specialists of Infectious Diseases – based on sound clinical evidence and data from literature, drugs containing the active ingredient favipiravir are capable of 'helping to inhibit the spread of the Covid-19 virus, thereby reducing the risk of the disease worsening and helping patients to recover as soon as possible,'" the MTI news release reads. There is no mention of the denunciation on the NIPN's website.

The "Association of Specialists of Infectious Diseases" evidently refers to the Infectious Diseases Section of the Association of Health Professionals. A letter sent on December 23, 2020 by Ildikó Horváth, State Secretary for Health, to Miklós Gondos, Director General of the National Healthcare Service Center (NHSC), on the availability of favipiravir in outpatient care, can be downloaded from the Association's website. (The NHSC was later dissolved on December 31, 2020, and its tasks were taken over by the then established National Directorate General of Hospitals, commonly known as Okfő.) The state secretary also refers to the protocol of the Infectious Diseases Section, the same one that the NIPN referred to more than a year later. This document, entitled "Principles for the management of confirmed COVID-19 patients", can also be downloaded from the association's website. In the document, favipiravir is listed as having "conflicting data".

Essentially, this recommendation, which was issued on December 23, 2020 and not updated since, was included in the Hungarian treatment protocol, which in turn is regularly updated, most recently on November 21 2021. It was then that new antivirals were added alongside favipiravir – something we'll come back to later. This same recommendation also notes for favipiravir that "clinical results on its efficacy are conflicting". From this alone, it is difficult to understand why the NIPN, who makes reference to this, considers the efficacy of favipiravir to be beyond dispute.

Although not strictly relevant to the topic at hand, it is worth comparing the Hungarian recommendation with the Australian one, for example: Hungary's is a 12-page pdf that had been printed out and then scanned in image format (so it is not searchable); Australia's recommendation is available in an interactive, searchable and click-through online interface – and the section on favipiravir, for example, includes a brief summary, the factors underpinning the recommendation and the sources that were used. (At least this Hungarian recommendation was updated in November 2021: the full Covid manual, of which the original is one chapter, reflects the status as of June 2020.) But even the Philippines has a clear, easy-to-navigate and regularly updated (most recently on January 10 2022) treatment recommendation, with detailed justification for each possible intervention, with reference to research findings. Favipiravir is described here as lacking sufficient evidence to recommend its use for covid patients. The recommendation is accompanied by a 19-page summary, also updated regularly and even indicates what has changed since the previous version.

Not only does the NIPN statement not cite a single scientific source, but neither does the Hungarian recommendation itself. We contacted the Infectious Diseases Section to find out their professional opinion on the content of the articles challenged by the NIPN, the research cited in them and the statements of the experts that were interviewed – whether they also consider them objectionable or whether they think they can be the subject of a legitimate scientific debate. We also wanted to know whether additional research not mentioned in the contested articles but published since the original recommendation of the Infectious Diseases Section had changed professional opinion on favipiravir and whether they think it is worth reviewing and updating the national recommendation on favipiravir and its use. We had not received a response by the time of publication of this article.

But when it came to RTL Klub, the NIPN gave a response. The pharmaceutical authority argued that favipiravir was effective, saying that data from primary care physicians showed "a 94 percent recovery rate." At first sight, this figure seems high, but it is still an odd claim. They are not talking about an efficacy rate – something that wouldn't be possible without a control group study – but rather about the recovery rate of patients treated with favipiravir. This in turn means that 6 percent of people receiving favipiravir were released from primary care as nonresponders, i.e. either hospitalized or deceased. Of course, this in itself does not tell us much because many important details remain unknown, such as the age of the patients who received favipiravir, the severity of their illness and when they started taking the drug. But 94% is by no means conclusive evidence that favipiravir is effective.

Naturally, we also contacted the NIPN with questions of our own. We asked them which articles in particular were of concern to them; which statements in those articles they objected to; what scientific evidence they considered to be misleading; and how to interpret this 94% cure rate. We even received a reply: it was word for word the same as the letter sent to RTL Klub, meaning that none of our questions were answered. The NIPN's letter read:

"The NIPN considers the legal resolution of this latest case of fake news important, as it continues to hamper the fight against the pandemic and undermine people's confidence in life-saving vaccines and medicines. We are constantly monitoring the effectiveness of favipiravir therapy. We already have over 70,000 records from primary care physicians on favipiravir use, with a cure rate of 94%. Hence favipiravir is very effective in the prevention of severe illness by inhibiting viral replication in the early stages of the disease."

How effective is it – and compared to what?

Even if the authorities didn't specify what research they were referring to in their announcement, there has indeed been a lot of research on the use of favipiravir against Covid-19 since the beginning of the pandemic. In recent weeks, a number of clinical trial results have been reported in newspaper articles as well as by experts. Part of these have focused on treatment of moderate to severe patients in a hospital setting, with mixed but rather negative results. However, given that domestic specialists arguing for the efficacy of favipiravir also stress that the drug is considered useful in the early stages of the disease and that the therapeutic protocol recommends it for mild-to-moderate patients, it is worth concentrating research on this target group (even if there may be overlap in the case of moderate patients).

In order to assess its effectiveness, it would be advisable to look first at the results of the meta-analyses. Such studies don't carry out any new clinical trials, but rather aggregate and analyze previously published results according to a common set of criteria so as to reconcile the findings. This ultimately gives a more comprehensive picture of a given topic. In the last six months or so, there have been three meta-analyses of the results of trials in patients with mild-to-moderate symptoms. We apologize in advance for what may be a bit of a dense paragraph, but it is important to present what exactly is known about this extensively used medicine.

One of the most widely cited international studies in the favipiravir debate (and the only one included in the articles that the NIPN presumably objected to) is an Iranian analysis published at the end of May 2021. It concluded that favipiravir did not statistically significantly reduce the need for intensive care or oxygen support, nor did it decrease the mortality rate compared with the control group. There was a statistically significant improvement in the patients' condition compared to the control group, but only when measured on day 7; by day 14 there was no such difference. The viral load decreased most on day 14 after the start of treatment, but not significantly. However, an addendum to the May 2021 study has been published because one of the studies analyzed has since been withdrawn due to suspected data falsification. The authors re-evaluated their results, and now, apart from a temporary improvement on day 7, favipiravir was no longer effective with regards to any indicator. The authors note that it may be too late to start taking the drug when symptoms appear.

Two further meta-analyses have been published since then. The first, a Japanese analysis which was also published in May 2021, concluded without retracted studies that the reduction in viral load is significant on day 7, so the drug may have a role in the treatment of mild to moderate patients, but further studies are needed to establish this clearly. It is worth noting, however, that this second meta-analysis analyzed four original studies for the reduction in viral load, while the updated version of the first one in May 2021 (i.e. without the withdrawn study) analyzed five: the same four plus one newer study. In other words, from this point of view, the meta-analysis published a few days earlier is in fact the more recent one, and it is precisely the extra study included in it that makes the previously established – and not even significant – positive effect of favipiravir on reducing viral load vanish.

The third meta-analysis in China was published in December 2021. It found that favipiravir significantly reduces viral load and hospital stay in mild to moderate patients. However, this meta-analysis also draws on two studies that were withdrawn due to suspected data falsification (one having been already mentioned above, and the other being a previous study by some of the same authors).

"Based on the evidence to date, favipiravir is likely to reduce viral load, but this effect depends to a significant extent on the time at which treatment is started, the dose administered and the duration of treatment."

– said academic Miklós György Keserű, head of the Medicinal Chemistry Research Group at the Centre for Natural Sciences and leader of the consortium developing favipiravir in Hungary. He added that "meta-analyses have a place in the scientific field, they can help in the design and successful implementation of further trials", but that "because they may differ in the criteria for the patients included and the parameters studied, such analyses are not accepted as conclusive by pharmaceutical authorities."

Although the above meta-analyses examined patients with mild to moderate symptoms, they did so in a hospital setting. However, there have also been studies specifically on the use of favipiravir in outpatient care, immediately following the onset of symptoms. In the first two studies, participants started favipiravir within three days of symptom onset, in the third within six days and in the fourth within five days. That is, in all but one case, administration of the drug was exactly in line with the national recommendation of 3-5 days:

• In November 2021, the Canadian drug company Appili Therapeutics reported that its large study of 1,231 people in three countries found no significant reduction in recovery time in the favipiravir-treated group.
• Also in November 2021, a US study of 149 patients concluded, "Our data do not support favipiravir use at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher doses of favipiravir are effective and safe for patients with COVID-19." The doses used in the study here were higher than those specified in the Hungarian recommendation.
• A Russian study published in November 2021 looked at the effect of favipiravir in both hospital and outpatient settings in patients with mild-to-moderate symptoms. Their findings showed that in the 127 outpatients who participated, the drug led to improvement in the time of recovery, but not in the time of viral shedding. (As for the other indicators, such as ICU admissions and deaths, they did not separate inpatients and outpatients, but the overall data showed that favipiravir did not improve these.)
• A study of 231 people in Saudi Arabia in January 2022 found that favipiravir therapy in mild COVID-19 patients did not reduce the time to viral clearance within 15 days of starting the treatment.

It is also worth mentioning a fourth study, which – rather than outpatients – examined mild to moderate cases in a hospital setting, among which were also high-risk patients. This Malaysian study of 500 people, published in November 2021, found that early treatment – initiated in the first seven days of onset of the disease – did not prevent the participants from becoming oxygen deprived. There was also a small US study of 50 people, published in December 2021, involving hospitalized patients with varying severity, including mild to moderate, in which the overall results showed that favipiravir accelerated the shedding of the virus.

In Hungary, only three clinical trials of patients with any degree of severity were planned, but only one of these was carried out, involving patients with more serious conditions who were hospitalized between March and July 2020. The preprint results were published in December 2020 and the final, peer-reviewed study was published in September 2021. Researchers from the National Institute of Hematology and Infectious Diseases at the South-Pest Central Hospital and Semmelweis University concluded, based on a study of 150 patients, that favipiravir has not been shown to have a positive effect on the course of the disease in patients with moderate to severe symptoms.

On paper, this amounts to the fact that, if anything, the drug is more likely to have a positive effect in mild to moderate patients. The other two domestic trials would have focused on such cases, but these were eventually abandoned (although the first one is still officially ongoing, according to the linked register). Gábor L. Kovács, chairman of the HECRIN consortium responsible for running the trials, told Qubit in December 2021 that the trials had been scrapped because a lot of favipiravir had become available in the interim and no doctor agreed to give their patients a placebo in place of the drug.

But effectiveness is not a question with a yes/no answer. The findings so far suggest that favipiravir may have a positive effect in the treatment of mild-to-moderate Covid patients in the right circumstances, but that this effect is very modest and the evidence is conflicting.

"The effectiveness of most drugs, including favipiravir, cannot be described by a set of discrete factors, but rather by a set of continuous ones. In other words, the possibilities are not merely effective/ineffective, rather every 'hue' on the scale between maximum and minimum effectiveness can arise. And at the moment, favipiravir finds itself in the pastel range of this scale. The therapeutic value of medicines is never absolute: it is always compared with other medicines that can be used for the same purpose. What may have seemed like purple last year may appear pale beige today," wrote Dezső Csupor, a pharmacologist and author of the popular science site Pirulakalauz.

"As such, we cannot claim that favipiravir is the most potent Covid drug in the world. And it would be a problem if it were."

"Hopefully they'll come up with something much better, much more effective, which is perfectly normal in pharmaceutical research."

It is therefore reasonable to argue that a moderately effective medicine for a potentially fatal disease is still much better than no medicine at all. But it is also legitimate to claim that if a drug that is clearly more effective comes along, the use of a moderately effective drug is less justified. In fact, two antivirals for the treatment of mild to moderate covid patients have now been shown to be more effective than favipiravir.

The arrival of a new generation of antivirals

Gábor L. Kovács, president of the HECRIN consortium responsible for clinical trials in Hungary, told Qubit that at this point, it would be "a pity to incur additional financial and social costs for the study of favipiravir, as there are antivirals on the market that have been proven to be more effective, such as molnupiravir".

The compound, molnupiravir, was originally developed for influenza, but was later made into a field-ready medicine for Covid-19 under the brand name Lagevrio, developed by two US companies, Ridgeback Biotherapeutics and Merck. The active ingredient is different, but the mechanism of action is virtually the same as favipiravir: it interferes with the replication process of the virus, thus preventing it from spreading.

Merck announced that, based on data provided by clinical trials at the interim analysis, molnupiravir reduced the risk of hospitalization or death by approximately 50%, which was very encouraging news. However, the data in the second half of the trial showed a reduction of only 3 percent, a huge difference. So overall, the drug reduced the risk by 31%, which is also not negligible, but a much more modest effect than expected.

As molnupiravir works in a similar way to favipiravir, there is also a risk of fetal side effects, and the US Food and Drug Administration (FDA) has also requested clarification of the potential bone and cartilage damage. The theoretical possibility has also been raised that, because the drug introduces mutations in the RNA of the virus, if the 'damaged' virus is not cleared from the body in time, it could potentially lead to the development of new variants, particularly in immunocompromised patients who are slower to shed the virus.

In any case, it was approved in the United Kingdom in early November 2021 and in the United States in late December 2021 for emergency use. An application for approval was submitted to the European Medicines Agency (EMA) at the end of November 2021, but a decision has yet to be made.

With that said, it is not this drug that represents a real breakthrough, but rather another, Paxlovid.

It was developed by Pfizer and because it has a completely different mechanism of action, it does not have the potential side effects of favipiravir or molnupiravir. Paxlovid is the brand name of the drug, and it uses two active ingredients that must be taken as separate tablets: nirmatrelvir, developed specifically to combat Covid-19, inhibits an enzyme that plays an important role in the replication of the virus; and ritonavir, which was originally used in AIDS therapy, slows down the degradation of nirmatrelvir. In other words, the first component accounts for the effect itself, while the second component is responsible for making the effect last.

In clinical trials, Paxlovid was found to reduce the risk of hospitalization and death by 88 percent when taken within five days of symptom onset. If taken within three days, it is 89 percent, so there was virtually no benefit to starting earlier, which is a very big win for real-world applications.

Paxlovid was approved in the United States on December 22 2021 and in the European Union on January 27 2022, but its significance is reflected by the fact that as early as mid-December the EMA had allowed Member States to use it in emergency situations.

"The priority in patient treatment is to always be able to offer the best therapy available. Until November 2021, this meant favipiravir and remdesivir. But things have changed, and that is why on November 11 we proposed a new antiviral treatment strategy and the domestic use of new medicines. The update to the therapeutic protocol, published on November 21, now recommends both new drugs for the treatment of mild to moderate patients," Keserű told Telex.

Similar to the case with favipiravir, Hungary's recommendation is to start taking both new medicines within 3-5 days, with the difference that they are only recommended for mild patients and only for those at high risk. It is worth noting that in this national guideline, molnupiravir is still rated at 50% efficacy.

"Given that there are more than 3 million unvaccinated people in our country and a significant number of groups at risk of Covid-19 due to comorbidities, the need for antiviral treatment remains high. For Paxlovid, there is no significant difference between the efficacy of treatment within 3 days and 5 days of symptom onset, but there is for molnupiravir. However, the US authorities' recommendation for both is to administer them as soon as possible, and strictly within 5 days. It is therefore important that testing is widely available, at least for high-risk groups, as this is a prerequisite for starting antiviral treatment in time, i.e. when symptoms appear," explained Keserű.

"Due to manufacturing capacity constraints, the new medicines are currently only available in Hungary in clinical trials, but once the supply issues are resolved, they are expected to become the first line of antiviral therapy. In pharmaceutical research, such changes are natural, as it is in the interest of all parties to ensure that patients have access to the most effective and safest therapies possible," he added.

There is one disadvantage that Paxlovid certainly has when compared to favipiravir: it is much more expensive. However, this does not seem to be an obstacle – at Thursday's government briefing, the Minister of the Prime Minister's Office, Gergely Gulyás, announced that the government plans to purchase 50,000 doses, a number that could be increased later.

Moreover, the various strains of the virus do not affect the efficacy of any of the antiviral drugs, i.e. they work in the same way against the more vaccine-resistant Omicron variant.

Confidence and the erosion thereof

The experts who expressed their scientific opinions on favipiravir, and the newspapers that interviewed them, are accused of undermining public confidence in medicines by the very same NIPN that authorized Sputnik V despite the negative opinions of the experts it consulted, and the Sinopharm vaccine on the basis of a government decree without any substantive examination. As released documents later revealed, there were serious professional concerns about both at the time. This surely did not increase confidence in vaccines, regardless of whether the early introduction of Eastern vaccines was otherwise epidemiologically useful. It is also doubtful that confidence in the vaccines is boosted by the fact that the NIPN has not issued a report on adverse reactions to Covid-19 vaccines since the beginning of the pandemic, while in many countries such reports are published regularly by the relevant authorities.

Public trust in the success of pandemic management is also not necessarily helped by the fact that, according to the report, it seems as if the pharmaceutical authority considers it abnormal and harmful for experts to question the use of a drug that was previously considered effective on the basis of later results. Yet not only is this not unusual, it is the normal way of things. Science works in such a way that initial results are later confirmed, clarified or even refuted by new research. This is especially the case with the evaluation of medicines, and it is precisely a testament that the system works, as it would be harmful to settle on the initial results and reject the new ones just because they lead to a different conclusion.

A case in point is the antimalarial drugs chloroquine and hydroxychloroquine. These were initially seen as very promising against the coronavirus. They were the drugs with the highest hopes, and US President Donald Trump was a particularly strong supporter. Then the initial enthusiasm was crushed by new results, and they have since disappeared from the list of potential coronavirus therapies, with the scientific consensus being that they are contraindicated for this purpose. The Hungarian recommendation also lists them in the "not recommended" category, alongside ivermectin, among others.

It is a common misunderstanding among the general public that if a scientist says something that diverges from something they had said before, either they must have been lying or they were mistaken. All that really happened was that they were open to updating their position on the basis of the new findings. And the NIPN is reinforcing this misconception of science by declaring a legitimate researcher's professionally established position to be fear-mongering because it contradicts a previously stated position.

"Frightening, unprecedented, shocking, nightmarish, disturbing"

Several researchers we spoke to condemned the approach of the pharmaceutical authority, i.e. the denunciation, but wished to remain anonymous due to the sensitivity of the subject. There were, however, some experts who publicly voiced their opinion.

"The NIPN should not be able to make use of criminal charges in a scientific debate as a means to get rid of its opponents with the police. The very idea of this is frightening, and I believe that the very prospect of it is an unprecedented attack on Hungarian academia" because it risks having the effect of "discouraging researchers from expressing their professional opinions for fear of possible prosecution. Consequently, the significance of this, in my opinion, far outweighs the effectiveness of favipiravir," wrote biostatistician Tamás Ferenci.

"It is extremely important to stress that this problem does not depend on who is right. Even if the NIPN proves to be right from start to end, and the two articles err from the opening line to the last, it is still unacceptable that the authority threatens to imprison researchers for expressing their opinion on a scientific issue based on their best knowledge and recent international research," Ferenci added in his opinion piece.

"The articles contain a number of inaccuracies, ranging from where the drug has been used, to the volume, circumstances and empirical data, both in terms of the clinical trials conducted and patient care. However, it is important to distinguish between the opinions of colleagues quoted in the articles and the text written by journalists. The opinions of experts necessarily have a place in an academic debate. When such a debate arises, it should be settled as soon as possible within a scientific context," Keserű told Telex.

Balázs Sarkadi, an academic and medical biochemist, who himself commented in one of the articles, called the move shocking and hoped that it was just the overzealousness of an official. In any case, he is ready to engage in a professional debate on the issue.

"There are tens of thousands of articles contained in scientific journals saying that one medicine is superior to another that is already on the market. The authors of these articles are not intimidated, threatened or even rewarded for their work, which is one of the driving forces behind pharmaceutical research," wrote Dezső Csupor.

According to Szabolcs Dobson, a pharmacist and drug licensing expert, "it's a nightmare that in 2022 in Hungary, even if in an insignificant and nonsensical form, an official attack could be launched on the freedom of scientific expression and the publication of scientific literature in peer-reviewed journals. [...] When it comes to the appropriateness of drug indications and the challenging of their efficacy in general, this sort of thing is a common occurrence in the industry's press. Many medicines have officially approved indications or other properties that are questionable and outdated both here and abroad. Revision of the pharmacopeia is a perpetual process. Not only are the medicines against Covid-19 no exception to this, they are all the more characterized by it, as their use in the context of the pandemic emergency has been based on very limited data and more and more robust test results are constantly being produced. It is precisely when these are disregarded and officials threaten to invoke their authority, the police or the courts – thereby forcing self-censorship not only on journalists but also on researchers – that serious harm can be done. It has a devastating and demoralizing effect."

The Hungarian Skeptic Society issued a statement on the matter. "The Skeptic Society considers it a disturbing practice, and one that should be avoided in the future, for any authority to use legal action to prevent the expression of scientifically sound critical opinions on matters of science. [...] We are well aware of the danger of those who try to manipulate the masses with claims that are often not scientifically substantiated, which is why we do not question the importance of sometimes taking legal action against fraud and deception," the society writes.

"But questioning the effectiveness of favipiravir is justified on the basis of an analysis of the scientific literature, and debating and discussing it (given that it is properly communicated) is not harmful, but beneficial and important, in part because it sheds light on how science is progressing. The discipline of science is constantly refining and correcting itself, and the journalists responsible for presenting it are doing their job well if they include the details, the questions and the uncertainties as well. To this end, it is important that they do not have to fear legal consequences just by doing their job."