Ramdesivir, hailed as cure for COVID-19: is history repeating itself?

The fear of imminent death due to COVID-19 has paralysed mankind across continents. Even as the World Health Organisation (WHO) and experts have begun saying that the coronavirus may never go away and that we better learn to live with it, the consternation is dimmed by reports that a vaccine, a cure, a medical protocol that works has surfaced somewhere or the other, keeping hope of immortality alive.

As a doctor, allow me to say that both these extreme outlooks are hugely exaggerated, more by design than by default. Let me explain why.

Anti-viral drugs, unlike antibiotics, are more of a hit and miss trial. Even as much of the world holds its breath and hopes for an anti-viral drug, the industry likely to profit from the breakthrough keeps the hope alive by providing encouraging results of the trials in progress.

Ramdesivir is in the news as the new miracle medicine to help us get rid of the scourge of the COVID19. A trial report was published in NEJM (New England Journal of Medicine) in April 2020. In less than a month, several countries have rushed to include the drug in their treatment protocol for COVID cases. By now it must have become a drug with maximum recall even among non-English speaking lay public. Expectedly, shares of Gilead Life Sciences have jumped by as much as 35-40% from its stock price in January.

Some 20 years ago, we witnessed the first outbreak of a coronavirus, SARS, at the turn of the century. Oseltamivir (Tamiflu) was then the new drug held out as a cure. Its production was licensed to Roche by Gilead in 1996. The FDA of the US approved the use of this drug for treatment of influenza in adults based on just two clinical trials in 1999.

In June 2002, the European Medicines Agency (EMA) approved Oseltamivir for prophylaxis and treatment of influenza. In 2005 SE Asia witnessed another corona virus (H5N1) outbreak –avian or bird flu. Panic mongers went on an overdrive and projected up to 200 million deaths. Governments across the globe stockpiled the drug worth billions of dollars in a bid to prepare to meet the pandemic. It turned out to be unnecessary and ended in an anti-climax. Deaths due to the bird flu epidemic did not exceed a few hundred.

In 2009 we had another outbreak of coronavirus, this time the Swine Flu(H1N1). In no time, the WHO declared the A/H1N1 influenza a pandemic. The National Institute for Health and Care Exellence (NICE), the CDC, the WHO, and the ECDC were also quick to recommend the use of Oseltamivir both for treatment as well as prophylaxis. WHO included the drug in the list of essential medicine.

A red flag was raised in 2009 itself by Keiji Hayashi, a Japanese physician. He pointed out that the key piece of evidence for the conclusion--that Tamiflu reduced the risk of secondary complications such as pneumonia--was based on a manufacture-authored, pooled analysis of 10 manufacturer-funded trials, 8 of which were unpublished.

The previous trials were subjected to a scrutiny by British Medical Journal (BMJ). Lead authors of the main Tamiflu treatment trials, as it turned out, did not perform an independent analysis of the primary trial data and relied mainly on the statistical analysis that had been conducted by Roche and they analysed the summary data instead.

Roche, in turn, stonewalled all requests by the Cochrane (the global repository of high-quality, relevant and up-to-date synthesized research evidence in medicine) investigators to share the data on the pretext of confidentiality or other similar grounds of obfuscation.

Frustrated, BMJ started what it called an open data campaign to help ensure access to these data for independent scrutiny, in order to support transparent and accountable analyses and decision making and not opaque and confidential data to govern public health.

Finally, in 2013, after years of campaigning the Cochrane reviewers got the full raw data based on which Cochrane review update was published in 2014. The reviewers concluded that there was no convincing evidence that Tamiflu affected influenza complications (in treatment) or influenza infections (in prophylaxis), and raised new questions about the drug’s potential for causing harmful side effects.

Later, it was revealed that scientists advising the WHO on its pandemic planning had done paid work for antiviral manufacturers—a serious conflict of financial interest that WHO had not publicly disclosed. Roche’s patent of the drug expired in 2016. In 2017, WHO downgraded Osaltimivir in the list of essential medicines. But by then the cash registers of the manufacturers had rung themselves to exhaustion.

Back to the present.

The two key trials of Ramdesivir have already been criticised on account of Lack of a control group, lack of randomisation, lack of a primary endpoint, lack of information about severity of the subjects, obscuring the signs of harm and last but not the least, being sponsored by the manufacturer.

NEJM- the journal that published the trial report—finds itself on the firing line from the scientific community. Still, the medicine is being included in the standard treatment protocol all over the world.

Is the story of Tamiflu to repeat itself? DCGI (Drug Controller General of India) has so far been more measured in its response. “It will be allowed to be sold in India only if it has a meaningful benefit”.

It is worth recalling the alert sounded by medical journal Lancet way back in 1998.

“The integrity of a body of literature is itself our society’s ultimate temporal forum for negotiating life and death, suffering and wellness... the medical wellbeing of the society it serves is dependent on the question of who stands behind the word.”