Today, the FDA authorized the emergency use of remdesivir for the treatment of patients who have Covid 19 symptoms severe enough to be given supplemental oxygen or placed on a ventilator. Remdesivir is an emergency treatment for severe cases of Covid 19 and is not a cure or a vaccine. https://www.fda.gov/news-events/press-announcements/coronavirus-covid-19-update-fda-issues-emergency-use-authorization-potential-covid-19-treatment
Let me start with the conclusion. According to the announcement of results from a NIAID study, Remdesivir appears to shorten the average recovery time in patients with severe Covid 19 symptoms. It does not appear to reduce fatalities and there may be adverse side effects. The benefit to patients with less severe symptoms of Covid 19 are unknown. Although any helpful treatment is welcome and needed, the actual impact of remdesivir is not clear.
The FDA issued the approval under the Emergency Use Authorization (EUA) . This allows the FDA to grant authorized use of medical treatments and products during medical emergencies which are NOT approved by the FDA under normal regulatory procedures. The EUA allows the FDA to approve a product for emergency use to short cut the time to market to address a medical emergency. EUA does not mean that the FDA has determined remdesivir to be safe and efficacious, but its ‘safe enough to try’ under emergency circumstances. The FDA grants EUA based on the information they have on hand to determine that the use of the product will be more likely be beneficial than harmful. There is no adequate, approved, and available alternative to the emergency use of remdesivir for the treatment of COVID-19. The authorization can immediately be withdrawn if on more widespread use, results are not favorable.
What is remdesivir? Remdesivir is a molecule that was developed in the pursuit of treatment of the Ebola Virus. Ebola Clinical trials with remdesivir were conducted in 2013-2016. Remdesivir was approved for Ebola treatment. In 2018-2019 another outbreak of the Ebola virus occurred but during that time remdesivir use was stopped when alternative drugs were found to be more effective. However, until this week, the clinical efficacy with humans with Covid 19 has never been established by accepted clinical trial protocols.
Remdesivir has had mixed results in treating Covid 19 patients with severe disease. Severe disease is defined as patients with low blood oxygen levels or needing oxygen therapy or more intensive breathing support such as a mechanical ventilator. Some reports seemed to indicate that remdesivir reduced the time to recovery for seriously ill Covid 19 patients, while other studies showed no benefit. None of the studies have shown a significant difference in fatality rates and some serious adverse events have been reported.
NIAID Study. Two recent reports of clinical trials have been recently reported. The National Institute of Allergy and Infections Diseases (NIAID) issued a preliminary report on a randomized, double blinded clinical trial comparing remdesivir with a placebo (a pill that looks like remdesivir but doesn’t actually have remdesivir in it) in 1063 Covid 19 patients. This type of study design is meant to minimize possible bias by the doctors, patients and other factors to make the best determination if the drug is better than doing nothing.
The group that received remdesivir recovered in an average of 11 days compared to 15 days for patients who received the placebo. The remdesivir group had a lower mortality rate than the placebo group (8% vs 11% respectively) but this difference was not statistically significant. This means that if a larger study is done, there is a chance that this apparent benefit will disappear. It is important to note that this was a summary report and the full details of the study have not yet been published, provided or peer reviewed.
It appears that the FDA provided the Emergency Use Authorization based on this data that, for seriously ill Covid 19 patients, remdesivir reduced the recovery time and average of 4 days (11 days vs 15) than patients who received no treatment. As the details were not provided, it is not known what percentage of the patients had their recovery reduced nor do we know the range of recovery times involved. We also do not know how the demographics of the patients in the trial compared to the general public in terms of age, gender, ethnicity, pre existing conditions etc. These details will hopefully be disclosed when the full study results are published.
‘China Study’ Almost simultaneously, a paper in the British medical journal Lancet, became the first published (the NIAID paper above has not been reviewed and published), peer reviewed article with a randomized, double blinded, multicenter clinical trial comparing remdesivir to placebo. Note: this paper is often referred to as the ‘Chinese Study’ as many of the authors were Chinese and the study was partially funded by the Chinese Academy of Sciences. However, the research was done by a collaboration of a large group of researchers from several universities in China, United Kingdom (Cambridge, Oxford) and the USA (Virginia) and funded by UK and USA sources as well. The full publication allows a more granular look at the actual data obtained in the study, not just the summary conclusion. I will include a more detailed discussion here to demonstrate issues that may be in the NIAIDS study once the full publication is provided. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)31022-9/fulltext
In the Lancet publication, 237 patients were at least 18 years old and positive for Covid 19 with severe symptoms. These symptoms were severe enough that the patient required supplemental oxygen or mechanical ventilation. Patients were admitted into the program within 12 days of onset of symptoms. Patients were randomly assigned in a 2:1 ratio to either the remdesivir (158 patients) treatment group of the placebo group (79 patients). Patients received an initial intravenous dose of 200mg (or placebo) on day 1 and then 100mg on days 2-10. The two outcomes assessed were clinical improvement and speed of recovery. It is important to note that the study was terminated before reaching the planned study end because of a higher incidence of severe adverse events in the remdesivir group.
| Remdesivir | Placebo | Statistical Difference |
|
|---|---|---|---|
| Time to improvement | 21 (13-28) | 23 (15-28) | NO |
| 28 day mortality | 22 (14%) | 10 (13%) | NO |
| Improvement Rate | 103 (65%) | 45 (58%) | NO |
| Adverse event - Stop Test | 18 (12%) | 4 (5%) | YES |
The patients in the remdesivir group had a numerically shorter average time to improvement (21 vs 23) , but not statistically different. (note: No statistical significance is an indication that the difference may be due to chance rather a true reflection of a difference). The mortality rates were the same. The clinical improvement rate was better for the remdesivir group but, again, the difference was not statistically significant. The one difference that was significant was that there were more complications with the remedesivir group that required that the remdemsivir be discontinued.
The paper concluded that there was no significant clinical benefit from treatment with remdesivir. A larger study would need to be done to confirm remdesivir has a shorter time to clinical improvement. It is important to note that there were only 237 patients in the trial and the trial was stopped short of completion. Nonetheless, there is so little remdesivir data available, the results should not be ignored. It is interesting to note that the time to clinical improvement range from 13-28 days for the remdesivir group and 15-28 days for the placebo group. This means that there people in the remdesivir group that were not helped and there were patients in the placebo group that recovered faster than the remdesivir group. This is the nature of clinical trials and why it takes larger numbers of patients over longer periods of time to determine true differences between groups. We can not judge the NIAID study until all the data is provided.
The conclusions on remedesivir are:
- The FDA has granted Emergency Use Authorization for remdesivir. This mean that physicians can use the drug if they deem it necessary for the care of patient with severe Covid 19 symptoms.
- The Emergency Use Authorization means that there is not enough data from clinical trials to grant approval but the FDA has determined that there is enough information to determine that the potential benefits of remdesivir out weigh the potential risks.
- The main benefit appears to be that remdesivir can shorten the recovery time by a few days in seriously ill Covid 19 patients..
- The results on this recovery time benefit were not consistently reported by the few other studies that have compared remdesivir vs placebo in a randomized control study.
- The full adverse effects are not known and in one study there were more severe adverse events in the group receiving remdesivir.
- There is a question of whether or not remdesvir lowers the fatality rate.
- More study is required and is on going. Some key unknowns how does remdesivir effect Covid 19 patients that do not have severe symptoms? What is the effectiveness as a function of patient age, gender and ethnicity? Is the current dose optimized? Will there be more adverse events as the number of patients is increased? Will some patients respond more positively of negatively due other existing medical complications?
Remdesivir may speed the recovery of patients with severe Covid 19 symptoms. The safety and efficacy are not known. This may help many people recover but will unlikely improve fatality rates and side effects are unknown.