During the COVID-19 pandemic, governments worldwide faced intense pressure to accelerate drug development while preserving scientific rigor. Japan’s experience with favipiravir (Avigan) stands as one of the example that illustrates how political enthusiasm, media hype, and regulatory ambiguity can lead to hasty decisions in times of crisis.
Favipiravir, developed by Fujifilm Toyama Chemical, was originally approved in Japan in March 2014 as an anti-influenza drug under exceptional circumstances.
Under normal regulatory standards, approval of the drug would not have been possible. Instead, it was authorized solely for government stockpiling, intended for emergency use during a novel or re-emerging influenza pandemic, and not for routine clinical distribution. In 2017, the Japanese government decided to stockpile favipiravir (Avigan®) as a novel influenza countermeasure for 2 million people.
When COVID-19 emerged in early 2020, favipiravir rapidly gained prominence in Japan as a domestically developed “hope drug.” From spring 2020 onward, mass media outlets repeatedly portrayed Avigan as a breakthrough treatment. This media narrative was followed by political endorsement.
Former Prime Minister Shinzo Abe publicly announced that the drug would be approved for COVID-19 treatment by May 2020, despite the fact that a phase III clinical trial had not yet been completed. This political declaration created a striking tension between social expectations and regulatory science. Unlike the media narrative, Japan’s regulatory authorities did not comply with the political timetable. Instead, they proceeded with a scientific review, ultimately declining to grant approval based on the available data.
In December 2020, the submitted data and a review report by the Pharmaceuticals and Medical Devices Agency (PMDA) were discussed by the Pharmaceutical Affairs and Food Sanitation Council (PAFSC). The council concluded that approval should not be granted at that time and that further review was required.
The core concern was in the design of the domestic phase III trial. Reviewers identified numerous shortcomings in the study. While Fujifilm argued that the study design had been agreed upon with regulators prior to trial initiation, the PAFSC determined that the evidence was insufficient.
As a result, Japan’s authorities decided that any future determination on approval would depend on data from ongoing overseas trials.
Dr. Reddy’s Laboratories, which was involved in two overseas phase III trials including one in Kuwait and another in Unites States, announced on January 27, 2021, that it had terminated the double-blind phase III trial in Kuwait and it is not yet approved in United States. It included an analysis of 353 hospitalized patients with moderate to severe COVID-19 and showed no statistically significant difference between favipiravir and placebo for the primary endpoint. Meanwhile, the company was continuing a PRESCO study in the United States, targeting patients with mild to moderate COVID-19. This trial was aimed to alleviate symptoms and prevent disease progression, with a planned enrollment of 826 patients.
The favipiravir episode revealed three major systemic issues.
Weaknesses in trial design awareness: Japan’s domestic phase III trial involved a small sample size, single-blinding, and subjective endpoints, apparently chosen to reduce cost and time compared with more rigorous double-blind trials conducted overseas.
Ambiguous regulatory criteria: The case highlighted the harm caused by inconsistent approval standards. While regulators ultimately prioritized scientific evaluation over political pressure during COVID-19. In 2014, at the time when favipiravir was stockpiled by the government for urgent measures despite poor results in the study conducted, those results should have been kept as considerations.
Lack of transparency: The regulatory process suffered from opacity. Despite widespread public interest, the PMDA’s review report was not made public, and the published minutes of the PAFSC meeting were largely redacted. Neither the 2014 influenza phase III trial nor the COVID-19 phase III trial completed in September 2020 had been academically published even by 2021. In a time when preprints and rapid data sharing became common during the pandemic, this absence of disclosure hindered independent evaluation and also fueled distrust.
Concerns over favipiravir’s use extended beyond regulators. On May 1, 2020, Medwatcher Japan submitted an “Opinion on Avigan (regarding COVID-19)” to the Minister of Health, Labour and Welfare. The group warned against the off-label use of Avigan for COVID-19 outside properly conducted clinical trials and urged caution in handling any approval applications.
These concerns culminated in a formal report issued on April 4, 2022, by the YAKUGAI Ombudsperson “Medwatcher Japan.” The report called for revoking Avigan’s approval and halting its stockpiling, citing unscientific decision-making, safety risks due to teratogenicity, and lack of demonstrated efficacy. According to the report, the favipiravir saga represented a regulatory failure driven by influence rather than evidence.
To date, there is no information about the cancellation of favipiravir stockpiling in Japan, and it is still stockpiled by the country for potential influenza outbreaks.
A 2024 study concluded that it is unknown whether favipiravir is efficacious in people with COVID-19, irrespective of severity or admission status. The study also noted that treatment with favipiravir may result in an overall increase in the incidence of adverse events, although not necessarily serious ones.
Similarly, a 2023 study reviewing repurposed direct-acting antivirals for HIV, HCV, and influenza such as lopinavir, favipiravir, darunavir, and danoprevir found limited or no clinical activity against SARS-CoV-2 across randomized controlled trials. These findings underline the lack of robust evidence supporting favipiravir’s use for COVID-19.
References:
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