The decision-making process for the launch of trials for COVID-19 repurposed antivirals

By Neha MathurMar 30 2023Reviewed by Danielle Ellis, B.Sc.

In a recent article published in the Annals of Internal Medicine, researchers reviewed the decision-making process for performing randomized clinical trials for three drugs under consideration for repurposing for coronavirus disease 2019 (COVID-19) treatment: remdesivir, molnupiravir, and tenofovir disoproxil fumarate (TDF).

Background

Two COVID-19 repurposed drugs, remdesivir, and molnupiravir, received their emergency use authorization (EUA) based on a single industry-funded phase III clinical trial launched after researchers collated adequate in vitro evidence of their effectiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Although substantial observational evidence by 2020 suggested that TDF users were at a much-reduced risk for severe COVID-19 than non-users, neither was TDF considered for randomized trials nor did it receive a EUA.

About the study

In the present study, researchers reviewed why the decision-makers favored launching randomized clinical trials for remdesivir and molnupiravir but not TDF. They aimed at helping the gatekeepers of randomized trials, i.e., government agencies, international non-profit organizations, and for-profit corporations, make good use of all available observational evidence for drug repurposing.

Why did remdesivir and molnupiravir make it into randomized trials but not TDF?

TDF is an inexpensive generic typically administered with emtricitabine (FTC) for HIV treatment and prophylaxis.

Clinicians found that HIV patients treated with antiretrovirals seldom progressed to severe COVID-19, and this observation prompted a randomized trial of TDF–FTC and other observational studies.

One observational study of 77,590 persons with HIV in Spain found that TDF–FTC users had nearly 50% reduced risk for COVID-19-related hospitalization. Another observational study performed among 536574 HIV patients reported a 58% lowered risk for COVID-19-related mortality among TDF–FTC users vis-à-vis abacavir–zidovudine users. Some studies even found a lower risk of COVID-19 diagnosis due to TDF–FTC use.

A phase II trial for TDF–FTC conducted in France among 60 people with mild COVID-19 found that TDF–FTC  use reduced nasopharyngeal shedding of SARS-CoV-2 substantially. Yet, this drug never moved into phase III randomized trials for COVID-19 treatment in non-hospitalized patients.

Findings and conclusion

The TDF case study demonstrated that the decision-making system favored conducting randomized trials for drugs with commercial value, like molnupiravir and remdesivir, but not for TDF-like generic drugs, which have limited commercial potential.

This case study also epitomizes general distrust and crucial misconceptions about observational studies, a weak justification but a key decisive factor for not initiating randomized trials for TDF. The non-profit funders were disappointed with inconsistent observational studies for hydroxychloroquine, which even some distinguished medical journals published, though later retracted. Even the researchers of some observational studies dismissed their findings.

In addition, confounding biases are likely in observational studies. However, there is a need to contextualize all concerns regarding confounding. Researchers channeled HIV pateints into TDF or other drugs, carefully adjusting for all confounding factors. Also, the measured confounding was insignificant owing to comparable adjusted and unadjusted estimates.

Thus, observational studies of TDF and severe COVID-19 among HIV patients did not fetch strong associations between TDF and lesser risk for severe COVID-19 inappropriately due to the absence of randomization.

Thus, complete disregard for observational studies is inappropriate. Instead, observational evidence should be considered, especially when the evidence points out strong associations, yet, if needed, reasonably rule out data but only after considering alternative explanations. #

In fact, huge investments of societal resources in randomized trials, including funding, volunteers, etc., requires that repurposing decisions incorporate all available evidence, including that from observational studies.

Based on these lessons learned from the TDF story during the initial two years of the COVID-19 pandemic, the researchers proposed some recommendations to guide decisions about drug repurposing of drugs with no commercial value for future public health emergencies. Firstly, public health organizations should maintain well-compiled databases of electronic health records for identifying suitable drug repurposing candidates.

Secondly, the agencies should ensure easy accessibility of these databases for specialized data analysis groups or academic researchers with the potential to develop apt drug repurposing assessments rapidly. Most importantly, decision-makers should consider observational evidence early for quick initiation of randomized trials.

In the context of antivirals, quick action is of utmost significance. For instance, it is unfeasible to test the feasibility of using TDF with nirmatrelvir in 2023 because anti-SARS-CoV-2 immunity is widespread and other treatments have become established.