Oseltamivir-Tamiflu fiasco serves as caution story for trusting remdesivir too early as coronavirus treatment
In 1999, the US Food and Drug Administration (FDA) approved oseltamivir and the drug was stockpiled in after pandemic scares in 2005 and 2009. But soon, things went wrong
Recent clinical trials involving the drug remdesivir have resulted in mixed results, but some experts are hopeful that the drug could be used to treat the COVID-19 virus. However, the news has resulted in many remembering the oseltamivir controversy. Oseltamivir was marketed and funded by the healthcare company, Roche.
There is currently no approved treatment or vaccine for COVID-19, which has killed over 238,780 globally as of May 1 in the pandemic. Worldwide, more than 3,340,400 cases have been reported, according to the Johns Hopkins tracker.
A trial conducted by the National Institute of Allergy and Infectious Diseases (NIAID), US, found that the drug accelerated the recovery time of COVID-19 patients by 31%, from 15 days in patients who got a placebo to 11 days in people treated with remdesivir. However, a second trial appeared to counter the results of the NIAID study as the median time to recovery for patients taking remdesivir was 21 days, compared with 23 days for those getting a placebo.
The conflicting results generated many reactions from scientists, and some are hopeful. “So in one well-conducted study (237 patients) of severe #COVID19, remdesivir was not effective, but it is reported to have some efficacy in a much larger study that has not yet been published. My hunch: remdesivir will likely have a role in treatment, but want to see the data,” tweeted Isaac Bogoch, infectious diseases physician and scientist at the University of Toronto.
However, the news on remdesivir trials has raised caution among many on social media who were reminded of the oseltamivir (brand name Tamiflu) fiasco which resulted in governments stockpiling on the drug after early positive results, only for the drug to be later revealed to having negative results.
One user tweeted, "It’s not that I don’t want to get excited by remdesivir; it’s just that I’m old enough to remember falling in love with oseltamivir and I can’t go through that again," while another wrote, "Like oseltamivir, remdesivir may not be 'worthless,' but may have more utility in early disease than in established severe disease."
How it started
In 1999, the US Food and Drug Administration (FDA) approved oseltamivir, a neuraminidase inhibitor, after randomized controlled trials, systematic reviews, and meta-analysis emphasized a favorable efficacy and safety profile.
Rising fears of pandemics in 2005 and again in 2009 led to recommendations by prominent regulatory bodies such as World Health Organization (WHO), Centers for Disease Control and Prevention, European Medicines Agency and others for its use in the treatment of influenza, which led to governments stockpiling the drug as a measure to tide over potential crises.
What went wrong
Serious adverse events were first reported during post-marketing surveillance from Japan, the UK, and subsequently from other places although most of the published articles did not report them.
A later review by the Cochrane Collaboration, a global not-for-profit organization of 14,000 academics found that the drug shouldn’t be used for treating seasonal flu, but was suitable for use as part of a suite of public health measures in pandemics.
This came after Dr Keiji Hayashi, a Japanese pediatrician questioned the Cochrane team regarding the results of their first review of oseltamivir, pointing out the fact that the conclusion of the study was not based on their own data analysis.
From 2010 to 2012, Cochrane requested Roche's full clinical study reports of their trials, which they did not provide. In 2011, a freedom of information request to the European Medicines Agency (EMA) provided Cochrane with reports from 16 Roche oseltamivir trials.
The renewed study by Cochrane claimed the drug did not prevent the spread of flu or reduce dangerous complications, and only slightly helped symptoms.
It was during this period that the global medical academic community began to understand that published academic papers on trials could be incomplete and even misleading. A more detailed report would the clinical study report (CSR), the intermediate document that comes between the raw data and a journal article. It details the plan for analyzing the data statistically, descriptions for adverse events, and so on. The bigger scandal, of course, is that this was not illegal.
In 2017, WHO downgraded the status of oseltamivir. At the time, Mark Ebell of BMJ wrote, "Removal of oseltamivir from the essential medicines list is better late than never, but still comes far too late."
Since then, many big drug companies announced policies to improve data transparency. Online databases, like alltrials.net, encourage researchers to register and share information from all their trials, not just the ones that end up published in medical journals.