As the number of COVID-19 cases continues to rise across the globe, reaching over 16 million confirmed cases in the months since the WHO declared it a pandemic in March 2020, countries continue to race against the clock to find a cure and protective vaccines.
Many healthcare decision-makers were taken by surprise by the pandemic, and in the absence of robust national pandemic preparedness strategies, have resorted to drastic and costly non-pharmaceutical measures known to control the spread of pandemic respiratory viruses. However, the high basic reproduction number (R0), and case fatality rate (CFR) of this novel coronavirus in older adults with underlying health conditions, has overwhelmed responses even in high-income settings. This has led to very long periods of national lockdown, closure of schools, travel restrictions, and to the shutdown of many vital economic activities. While protective vaccines are developed, researchers around the world have focused efforts on finding effective treatments, with drug repurposing featuring as the fastest, most viable, and least costly option. In a context where global cooperation is needed perhaps more than ever before, how concerned should we be by efforts to “stockpile” potential treatments, and how can we encourage further cooperation? We look at the case of dexamethasone and remdesivir.
A tale of two drugs
Drug candidates identified for repurposing were chosen based on historical evidence of activity against coronaviruses and similar RNA viruses, either in-vitro or during earlier outbreaks. The first two candidates that have shown promise are low-dose dexamethasone and remdesivir. Aside from having different mechanisms of action, these two drugs also differ in relation to their likely position in therapy, mode of administration, relative efficacy compared to the current standard of care, and, most importantly from a resource allocation perspective, price.
Dexamethasone, a corticosteroid, has been used since the early 1960s to treat a wide range of conditions, such as rheumatoid arthritis and asthma. It is a generic drug that is currently available in both oral and injectable forms. The regimen trialled in hospitalised COVID-19 patients is 6mg once daily for 10 days administered intravenously. The results from the RECOVERY trial showed that, compared to usual care, 482 patients (22.9 percent) in the low-dose dexamethasone plus usual care group and 1110 patients (25.7 percent) in the usual care group died within 28 days (age-adjusted rate ratio, 0.83; 95 percent confidence interval [CI], 0.75 to 0.93; P<0.001). In subgroup analysis, dexamethasone reduced 28-day mortality by one-third in ventilated patients (rate ratio 0.65 [95 percent confidence interval 0.48 to 0.88]; p=0.0003), and by one fifth in other patients receiving oxygen only, though this arm included patients on non invasive mechanical ventilation including high flow oxygen not readily available outside HIC hospital settings (0.80 [0.67 to 0.96]; p=0.0021). This clear mortality benefit has led to optimism about the potential of not only managing severe COVID-19 and reducing its mortality, but also doing so with an affordable and widely accessible treatment option that will not deplete healthcare budgets across the globe—at least for those countries with sufficient high dependency and intensive care facilities. Dexamethasone wholesale acquisition cost for a 10-day course of once-daily administration of 6mg tablet is approximately $15 in the US.
On the other hand, remdesivir is a branded drug manufactured by Gilead Sciences and was originally developed to treat Ebola virus disease. The regimen trialled in hospitalised COVID-19 patients was intravenous (IV) administration of 200 mg on day 1 followed by 100 mg on days 2 to 10. It was compared to usual care in a company-sponsored, randomised trial, the results of which showed a reduction in median recovery time (11 days (95 percent confidence interval [CI], 9 to 12), as compared with 15 days (95 percent CI, 13 to 19) in the usual care arm) and in 14-day mortality [Hazard Ratio (HR): 0.70 (95 percent CI: 0.47–1.04)]. The trial was criticised for a change in its primary endpoint (with only about 15 percent of patients having their outcome determined at the specified 28 days) and early termination. Another randomised placebo-controlled trial of remdesivir, however, showed that its use was not associated with a difference in time to clinical improvement (HR: 1.23 [95 percent CI 0·87–1·75]). This trial was also prematurely stopped for lack of patients to recruit as the outbreak in China was being controlled. Both studies show that uncertainty about the effect of remdesivir still exists. Gilead Sciences has since priced remdesivir at $2,340 for 5-day course for governments in developed countries.
Recently, news has circulated of the US stockpiling remdesivir by buying over 500,000 doses which is all of the manufacturing company’s production for July and 90 percent of August and September production. This move has been forecast to deprive the UK, Europe, and many other countries from access to this treatment for the next 3 months. It has been met by anger and scepticism around the world and prompted Gilead Sciences to issue a statement noting its intention to increase its manufacturing capacity to ensure adequate supply; it was also reported that Gilead intended to donate a supply of the drug to Australia’s national medical stockpile ahead of approval. In the end, the Australian regulatory authority granted provisional approval for remdesivir on 10th July, with an indication that focuses on severely ill hospitalised patients requiring supplemental oxygen.
But should this concern other countries?
The evidence-based answer is, “possibly not.” This is because, in terms of cost-effectiveness and based on back-of-envelope calculations, remdesivir could be a “dominated option” in patients who can instead be prescribed low-dose dexamethasone, if one accepts remdesivir lacks an effect on mortality. Put simply, remdesivir could be less effective and more costly in a head-to-head comparison with low-dose dexamethasone in hospitalised patients who require oxygen or mechanical ventilation. Based on its pivotal trial results, remdesivir was equivalent to usual care in its effect on mortality in hospitalised COVID-19 patient requiring respiratory support. This does not, of course, account for adverse effects, of either drug.
The US Institute of Clinical and Economic Review (ICER) initially estimated the fair or value-based price (VBP) benchmark of remdesivir to be $4,450 for a full course of treatment assuming a benefit on mortality based on the mean estimate from its pivotal trial (HR= 0.7). However, following the announcement of the low-dose dexamethasone results in June 2020, it became clear that this “fair” price needed to be revised. In response, ICER released its updated estimate that took into account the RECOVERY trial results for low-dose dexamethasone, on 24th June. ICER’s updated VBP benchmark (maximum of $2,800) was almost half the original estimate ($4,450) under best case scenario conditions which assumes a mortality benefit. Of note, ICER calculated this benchmark based on a cost-effectiveness threshold of $50,000 per quality-adjusted life-year gained, a value that is orders of magnitude higher than what would be applied in most countries around the world. The final price announced by Gilead Sciences for a course of six vials of remdesivir in the US is $2,340.
The table below depicts the updated cost-plus and value-based calculations of the Institute for Clinical and Economic Review (ICER) price benchmarks under different scenarios.
So far, remdesivir has not shown benefit in any other group of hospitalised COVID-19 patients. In a possible bid to demonstrate better value, Gilead Sciences started assessing its potential for use in the earlier stages of the symptomatic phase of COVID-19, in an easy-to-administer form (inhalation) as opposed to intravenous infusion as currently used.
Thus, we believe (and others agree) that payers should not consider stockpiling remdesivir to avoid repeating the mistakes made with oseltamivir and zanamivir during flu outbreaks. So far, no remdesivir study has definitely demonstrated any reduction in hospital stay or mortality. The benefit-risk balance of remdesivir is also still to be confirmed, with reports emerging of liver damage in COVID-19 patients treated with the drug.
If remdesivir proves to be a clinically effective but unaffordable option, the UK and other high-income countries could, if need be, secure supplies of remdesivir through a compulsory licence. This compulsory licence overrides the patent rights of Gilead Sciences and allows buying from generic manufacturers in countries like Bangladesh, Egypt, and India, where remdesivir production has already started and its price has been set at almost 80 percent of that in the US.
Given the above, we should resist suspending the application of basic principles underlying good evidence-informed judgements. The US decision to stockpile the drug at a higher-than merited price ignores potentially high opportunity costs for the health of its own population. The rest of the world should not feel compelled to do the same and should choose wisely.
The US decision to stockpile remdesivir sets a bad precedent in relation to issues of access for any upcoming vaccines and other COVID-19 supplies at a time when global cooperation is needed. This action will create black markets for the treatments, a rise in the supply of substandard and falsified medicines, and profiteering. But most pernicious of all, it will lead to misery for families of ill people, especially in poorer countries that lack universal health coverage, who will have to pay for these treatments themselves.