The decision-making process for starting trials for repurposed antiviral drugs for COVID-19

In a recent article in the Annals of Internal MedicineResearchers reviewed the decision-making process for conducting randomized clinical trials for three drugs being considered for repurposing to treat coronavirus disease 2019 (COVID-19): remdesivir, molnupiravir, and tenofovir disoproxil fumarate (TDF).

Study: Drug Repurposing and Observational Studies: The Case of Antivirals for the Treatment of COVID-19. Image source: marketolog/Shutterstock


Two repurposed COVID-19 drugs, remdesivir and molnupiravir, received their Emergency Use Authorization (EUA) based on a single industry-funded Phase III clinical trial, which started after researchers had sufficiently collated in vitro Evidence of their effectiveness against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Although significant observational data through 2020 suggested that TDF users had a significantly lower risk of severe COVID-19 than non-users, TDF was not considered for randomized trials, nor did it receive an EUA.

About the study

In the present study, the researchers examined why decision-makers preferred to start randomized clinical trials for remdesivir and molnupiravir, but not for TDF. They aimed to help the gatekeepers of randomized trials, ie government agencies, international non-profit organizations and for-profit companies, to make good use of all available observational data for drug repurposing.

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

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

Clinicians noted that HIV patients treated with antiretroviral drugs rarely progressed to severe COVID-19, and this observation prompted a randomized trial of TDF-FTC and other observational studies.

An observational study of 77,590 people living with HIV in Spain found that TDF-FTC users had an almost 50% reduced risk of COVID-19-related hospitalizations. Another observational study conducted in 536,574 HIV patients reported a 58% reduced risk of COVID-19-related mortality in TDF-FTC users compared to abacavir zidovudine users. Some studies even found a lower risk of a COVID-19 diagnosis due to the use of TDF-FTC.

A phase II study for TDF-FTC conducted in France among 60 people with mild COVID-19 found that the use of TDF-FTC significantly reduced nasopharyngeal shedding of SARS-CoV-2. However, this drug has never entered randomized phase III trials for the treatment of COVID-19 in non-hospitalized patients.

Findings and conclusion

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

This case study also embodies general distrust and crucial misunderstandings about observational studies, a weak justification but a crucial factor for not initiating randomized trials for TDF. The nonprofit funders were disappointed by conflicting observational studies on hydroxychloroquine, which even some respected medical journals published but 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 any concerns about confounding. Researchers initiated HIV patients on TDF or other drugs and carefully adjusted for any confounding factors. The measured confounding was also not significant due to comparable adjusted and unadjusted estimates.

Therefore, observational studies of TDF and severe COVID-19 in HIV patients did not find strong associations between TDF and a lower risk of severe COVID-19 due to the lack of randomization.

Therefore, a total disregard for observational studies is inappropriate. Instead, observational evidence should be considered, particularly when the evidence suggests strong associations, but reasonably excluding data where necessary, but only after considering alternative explanations. #

Indeed, huge investments of societal resources in randomized trials, including funding, volunteers, etc., require decisions to repurpose all available evidence, including that from observational studies, to be considered.

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

Second, agencies should ensure that these databases are easily accessible to specialized data analysis groups or academic researchers with the potential to rapidly develop appropriate drug reuse assessments. Most importantly, decision makers consider observational data early to initiate randomized trials quickly.

When it comes to antivirals, acting quickly is of the utmost importance. For example, it is not possible 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.

Written by

Neha Mathur

Neha is a digital marketing expert based in Gurugram, India. She holds a Masters degree from University of Rajasthan with specialization in Biotechnology in 2008. She has experience in pre-clinical research through her research project in the Department of Toxicology at the renowned Central Drug Research Institute (CDRI), Lucknow, India. She also has a certification in C++ programming.


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