Favipiravir, the brand name of Avigan and was first developed in Japan. The official English translation of the PMDA's review report on Avigan's indication for influenza is here.
This review report has a very unusual logic to it. In summary;
- It has no clinical significance for any flu tested.
- However, it may work against the unknown flu, but they don't have any evidence.
- So when any existing drugs don't work, if the government requested, that can be used. Approval is for that purpose.
- However, the results of animal studies strongly suggest that Avigan is a dangerous drug, so it must never be used until the government says it is OK to use it.
The review report pointed out the harmful effects of avigan; the following two are especially remarkable.
- Even when daily doses were about the levels of clinical use, 9 of 12 young canines died within 30 days.
- Avigan is teratogenic.
The minutes of the Review Board's deliberations against Avigan to the flu is the
'Minutes of February 3, 2014' (Written in Japanese).
You can read out Review Board member's various objections from the above meeting-minutes. However, they did not overturn this approval for the following reasons;
- Avigan will never be distributed without the government's order.
- Crisis management was not an area of expertise of this review board
There are two clinical studies in Japan for Avigan to the COVID-19.
One is the study led by the Fujita Health University in Japan.
- jRCTs041190120 :Multicenter, open-label, randomized trial of favipiravir in asymptomatic and minimally symptomatic patients infected with SARS-CoV2 to evaluate viral load reduction
Normally, such studies should be called intervention studies, but they are treated as observational studies for some reason. I don't know the details, but apparently, observational studies simplify the legal process.
This appears to be running as part of a registry study(Written in Japanese) on COVID-19.
That interim report of Fajita study is here.
In response to this study, a non-profit organization on drug abuse in Japan has written thisreport (Written in Japanese).
In brief, the mortality rate of corona-affected patients who received Avigan in the Fujita study is much higher than that of corona-affected patients in the real-world data. As real-world data, they used the "Japanese Ministry of Health, Labor and Welfare's Guide to Medical Care of New Coronaviruses, Version 2.1" and the "China CDC's data."
The trial has already been completed, The registry still says "recruiting" (probably due to a delay in updates) as of November 1, 2020. In July 2020, they published a webpage (Written in Japanese) on the website of Fujita Health University. That is a briefly report of the final results of the study. The webpage states that "no one became seriously or died during participation in the study". But this description seems to contradict the earlier interim report.
(2)Phase III Clinical Trial by Fujifilm
The clinical trial registry for the Phase III Clinical Trial, titled "Phase 3 Clinical Study of Favipiravir in Patients with COVID-19 Non-Severe Pneumonia" is here
The newspaper article (Written in Japanease) states;
- The median time to negative SARS-CoV-2, the primary endpoint, was the primary endpoint. The results of the study showed that the median time to negative SARS-CoV-2 was 11.9 days in the intervention group and 14.7 days in the control group, which was significantly reduced by Avigan (p=0.0136, adjusted hazard ratio: 1.593, 95% confidence interval: 1.042-2.479). ).
- No serious side effects were identified, and no new safety concerns were identified.
- The company plans to submit an application to Japan's Ministry of Health, Labour and Welfare for approval by October 2020.
The article also says the independent committee recommended that the number of subjects, originally planned to be 96, be increased to 156 considering the interim report results. Increasing the sample size would make it easier to detect even a small difference as significant, but I doubt the p-value is still greater than 0.01.
Furthermore, there is no mention of hard endpoints, such as preventing severe disease or reducing mortality. The animal study data in the PMDA's review report strongly suggests that Avigan is a dangerous drug. Even in the Fujita study data, the mortality outcomes appear to be worse than the real-world data.
However, chatting with other Japanese peoples, the lower education levels in Japan seem to feel a strong sense of patriotism towards Avigan; they feel that Avigan is like a miracle hero. In addition, the Japanese government at the time seems to have been taking a proactive stance in approving Avigan.
According to the convention, the PMDA would make a decision in November 2020.
In my personal discussions with my friends (they are highly educated), many think that the PMDA will probably be approved because the government and public opinion can influence it.