On April 17, 2021, the Government of India decided to review the prices of Remdesivir (GS-5734™ or Veklury®) in the country. However, the most sought after drug during the current COVID-19 crisis is also being sold in the black market for desperate patients, while social media is inundated with requests for Remdesivir.
Remdesivir is a patented antiviral drug by Gilead (US). It was initially developed to treat viral hepatitis, and a cold-like virus called respiratory syncytial virus (RSV) but was later studied for antiviral activity against several viruses. Remdesivir wasn’t an effective treatment for either disease. However, some initial responses against other viruses made the FDA approve this drug to treat COVID-19 as a first.
Currently, the Indian pharmaceutical giants Hetero labs and Dr Reddys sell the drug for just under Rs. 5000 per vial. Each vial is given per day for at least 5-10 days to hospitalised patients amounting to a significant economic burden on the patient. While not all hospitalised patients are getting the drug, it is administered extensively by the clinicians. In some cases, it is given upon the request of desperate patients. The belief that Remdesivier is the best available drug has turned people to hoard it, resulting in an acute shortage throughout the country.
Guidelines for Remdesivir use in other countries
Despite the US FDA approval, Remdesivir is not administered as extensively in other countries. For example, the NHS in the UK has clearly updated guidelines regarding its use such as eligibility criteria of only COVID-19 hospitalised patients those who clinically classify as suffering from pneumonia and require supplemental oxygen. It is also given in the early days during the onset of the symptoms, only to patients with age greater than 12 and over 40 kgs in weight, with an eGFR of at least 30 ml/min and ALT below 5 times the normal baseline of healthy people. eGFR & ALT are tests to assess kidney and liver function respectively.
In India, the Ministry of Health also recommended it as an investigational therapy in their COVID-19 management protocol document and tweeted that “it is not a life-saving drug”. Despite that, it is widely used as the drug of choice for most hospitalised COVID-19 patients. As sources dwindle, COVID-19 patients have been struggling to procure it, but scientists have raised questions about the efficacy of Remdesivir. In July 2020, the ICMR and AIIMS suggested against the indiscriminate use of Remdesivir, but the ICMR has not released a written set of COVID-19 protocols under which the drug can be given only to those who clinically qualify for it.
Scientific research is not analysed by the observance of effects in one or two people who have recovered after taking a drug. To deduce a high quality of scientific evidence, multiple studies on a large number of people are assessed together – called a systematic review. Here, we conduct a systematic review of four Randomised Control Trials (RCTs) conducted for Remdesivir (Veklury) and present the final higher quality evidence of its efficacy.
Claim: Remdesivir is effective in treating all COVID-19 patients
Studies 1 & 2 showed Remdesivir cannot treat COVID-19.
Study 1: Wang, Yeming, et al. “Remdesivir in adults with severe COVID-19: a randomised, double-blind, placebo-controlled, multicentre trial.” The Lancet 395.10236 (2020): 1569-1578.
This study, published in April 2020, was the first double-blinded, placebo-controlled, randomised clinical trial (RCT). It was also a multicentre trial with ten hospitals in China with 237 patients. 158 of them were given Remdesivir, and the rest were given a placebo, while they were on other forms of COVID-19 protocol treatments. Despite a low sample size, the study found no significant differences in patients treated with Remdesivir in comparison with the placebo treatment.
Study 2: Spinner, Christoph D., et al. “Effect of remdesivir vs standard care on clinical status at 11 days in patients with moderate COVID-19: a randomized clinical trial.” Jama 324.11 (2020): 1048-1057.
Another study devised a slightly different testing methodology. Study 2 was published in September 2020 by scientists from 23 institutions globally (GS-US-540-5774 Investigators). The experiment was to study the effect of 5 and 10-day dosage in about 584 hospitalised patients of 46-66 years, both males and females, with a mix of comorbidities like hypertension, diabetes and cardiovascular disease. While the five-day dose group showed better clinical improvement on day 11, the ten-day dose group showed no differences with standard care of treatment. However, the improvement in the five-day treatment group was only a tiny change. By day 28, a total of nine patients had died from all three groups, i.e. 5 and 10-day group and the placebo-controlled group receiving standard care. However, many reported side effects frequently observed in the Remdesivir groups, include nausea, hypokalemia, and headaches.
Study 3 showed Remdesivir shortens COVID-19 recovery time.
Study 3: Madsen, Lone Wulff. “Remdesivir for the Treatment of Covid-19-Final Report.” The New England Journal of Medicine 338.19 (2020): 1813-1826.
In November 2020, American scientists conducted another RCT (ACTT-1 Study Group Members) with opposing results regarding recovery times. In 1062 patients with 541 assigned to Remdesivir and 521 to placebo, those who received Remdesivir had a median recovery time of 10 days (max 11) compared with 15 days (max 18) among those who received placebo. Thus, Remdesivir patients were more likely to get clinically better at day 15 than the placebo patients, indicating that the drug improved recovery periods.
The mega Solidarity trial (study 4) by WHO that tested the effect of Remdesivir against COVID-19
Study 4: WHO Solidarity Trial Consortium. “Repurposed antiviral drugs for COVID-19—interim WHO SOLIDARITY trial results.” New England Journal of Medicine 384.6 (2021): 497-511.
This was also called the Solidarity trial and was the most prominent trial for Remdesivir and other drugs administered during hospitalisation of a COVID-19 patient, funded by the WHO. This trial was published in February 2021 and was the most extensive study conducted so far of Remdesivir. It included data from a vast sample size yielding a high power in scientific validity with more than 11,000 patients. In the figure, Remdesivir performs no better than control for in-hospitalisation mortality, which means that the drug cannot prevent COVID-19 related deaths.
Since it is an ongoing trial with the WHO, it has exceeded 12,000 participants, with a ‘Solidarity II’ underway for serological testing. The published trial included 30 countries, over 500 hospitals in all six regions of WHO with consistently matched comparable groups with objective outcomes. The primary consideration was that this trial was not funded by a pharmaceutical company or someone with a monetary interest in the drug industry.
One of the limitations of this trial could be that the sub-groups only had 8% ventilated patients, which is a huge consideration to determine the severity of COVID-19. A second limitation was that there was no ongoing symptom data from patients across the 28-day period. Although the effect of the drug on mortality and the hospital duration was considered the outcome in the drug trial, the study demonstrated that Remdesivir neither changed mortality nor the duration of hospitalisation in such a massive sample of COVID-19 patients (see figure above from the Solidarity trial).
Gilead Sciences, marketing and the lucrative market of Remdesivir
Meanwhile, Gilead signed an over a billion-dollar deal of Remdesivir with the EU Commission before the extensive interim data of the WHO Solidarity trial (Study 4) was released and ruled out the lack of efficacy on COVID-19 mortality Remdesivir. Gilead quoted that the WHO trial was not rigorously reviewed, and the trial design might hold limitations to testing the drug.
Gilead also quoted study 3, or the ‘ACTT-1 Study’ that favoured the role of Remdesivir in COVID-19 patients hailing it as the gold standard for testing efficacy and safety of the drugs.
Meta-analysis- a part of systematic review for Remdesivir
A meta-analysis assesses the data of many human trials (RCTs) in similar conditions of the same drug to determine the higher value of scientific evidence. Pooled data (see image) from the four significant trials, i.e study 1,2,3 and 4 above, across the world shows a modest amount of variability in the efficacy measured. (source: Dr Mike Johansen). This analysis is based on a ‘random-effects model’, which assumes a distribution of treatment effects or the average treatment effect across the studies. The higher the i-squared, the greater the difference of effects between groups, but a higher weightage is given to the study with larger sample size, i.e. WHO Solidarity trial 2020, and while the higher i-squared score could be a result of study 3, i.e NEJIM, 2020.
So why did one study (study 3) report different results?
Clinicians have pondered on this since the ACTT-1 study was published earlier than the Solidarity trial. Some of them suggest that it could be due to a clinician bias while prescribing Remdesivir with a belief that this is the best drug in the market for COVID-19. The FDA clearance and a marked up media highlighting the popularity of the drug prior to the publication of its research could also be the reason why human cognitive biases could have added to the ‘placebo effect’ in a small number of patients. Such examples of biases were reported on Twitter by clinicians prescribing Remdesivir in the light of newly available Solidarity trial data.
Effects on biochemical activity of coronavirus
Study 5: Kokic, Goran, et al. “Mechanism of SARS-CoV-2 polymerase stalling by remdesivir.” Nature communications 12.1 (2021): 1-7.
In a petri dish or an ‘ex-vivo’ study, the drug has also shown some antiviral activity in several other viruses, as well as biochemical studies that suggest it has a strong RNA polymerase inhibition of coronavirus. RNA polymerases are crucial in the replication cycle, and inhibiting their activity can be a robust mechanistic that leads to further the research of antivirals against SARS-CoV-2. As a result, many drug companies such as ‘Creative Biolabs’ are trying to create RNA polymerase inhibitor drugs against COVID-19.
Many drugs show efficacy in ‘ex-vivo’ or outside a living body, whether animal or humans, but not many go through showing efficacy in animals and humans. However, at this point of the pandemic (April 2021), Remdesivir has shown no effects on mortality in human clinical trials related to COVID-19.
Despite many extensive studies testing the effect of mortality and duration of hospitalisation, Remdesivir remains ineffective for most COVID-19 patients. It is still being used in patients for five days for those requiring oxygen, suggesting it can impact clinical improvement given very early during the disease to those requiring oxygen (see further guidelines as per the NHS, UK here), but it may not prevent deaths. However, we are yet to see the effects of those in which Remdesivir is given exclusively in comparison with those who require supplemental oxygen and pneumonia patients.
Since the large Solidarity trial itself suggests the lack of Remdesivir efficacy, the pooling of RCTs (meta-analysis above) strengthens the Solidarity data. It is possible that the pharmaceutical companies have promptly promoted drug efficacy during the global second wave and sought multimillion-dollar deals with different governments. However, in the light of this analysis, the desperation in acquiring Remdesivir specifically for economically underprivileged patients can prove difficult given that a 10-day course can be anywhere over Rs. 35,000 per patient. However, it can be used as a drug for a five-day period with those requiring oxygen and hospitalisation instead of prescribing it liberally as it is being done today. It may add to mild differences in clinical conditions if given at the right time.
The approval by FDA has made it nearly impossible to set up a placebo vs Remdesivir trial as physicians would find it ethically challenging to randomise patients to placebo. Additionally, its adverse effects’ profile tilts the scales against its rampant, uncontrolled use in COVID-19 patients. It makes little scientific sense to suggest that it is a saviour drug against SARS-CoV-2 infection.
However, clinicians on the frontline would struggle to refuse the use of the drug, which has FDA regulatory approval status. Also, media sentiment has exploited the end-user desperation for a cure and has played a role in elevating the position of the drug in excess of what evidence would allow. A plausible reason for its continued use can be a lack of well researched, updated and unambiguous guidelines for the clinicians from any central body. Other reasons, such as economic gains or conspiracy theory, are beyond the scope of this analysis.
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