Remdesivir and Molnupiravir, two COVID-19 repurposed medications, received their emergency use authorization (EUA) based on a single phase III clinical trial funded by industry that was started after researchers gathered sufficient in vitro evidence of their efficacy against severe acute respiratory syndrome coronavirus 2. (SARS-CoV-2).

Although there was strong observational evidence by 2020 showing TDF users had a significantly lower probability of developing severe COVID-19 than non-users did, neither randomized trials nor an EUA were considered for TDF.

Researchers examined why the decision-makers preferred starting randomized clinical trials for remdesivir and molnupiravir but not TDF in the current investigation. They wanted to assist the entities that serve as the gatekeepers of randomized trials, such as governmental bodies, global non-profits, and for-profit businesses, in making effective use of all available observational evidence for drug repurposing.

TDF is a cheap generic drug that is frequently used in conjunction with emtricitabine (FTC) for HIV prophylaxis and treatment.

Clinical trials with TDF-FTC and other observational studies were driven by the discovery that HIV patients on antiretrovirals seldom advanced to severe COVID-19.

TDF-FTC users had a roughly 50% lower incidence of COVID-19-related hospitalization, according to an observational study of 77,590 HIV-positive individuals in Spain. Another observational research with 536574 HIV patients found a 58% reduction in viral loadThe 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.