Decision-making process for trial initiation of COVID-19 repurposed antiviral drugs

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

Background

Two COVID-19 repurposing drugs, remdesivir and molnupiravir, received Emergency Use Authorization (EUA) based on a single industry-funded Phase 3 clinical trial that was initiated after being well matched by researchers . in vitro Evidence of efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

By 2020, substantial observational evidence suggested that TDF users had a significantly lower risk of severe COVID-19 than nonusers, but TDF was not considered for randomized trials. , and did not receive an EUA.

About research

In the current study, researchers examined why decision makers favored initiation of randomized clinical trials of remdesivir and molnupiravir and not TDF. They aim to help the gatekeepers of randomized trials, namely government agencies, international non-profit organizations, and commercial enterprises, to take advantage of all available observational evidence for drug diversion. There was

Why did remdesivir and molnupiravir enter randomized trials but not TDF?

TDF is an inexpensive generic drug that is usually given with emtricitabine (FTC) for the treatment and prevention of HIV.

Clinicians have found that HIV patients treated with antiretroviral drugs rarely progress to severe COVID-19, an observation that prompted the TDF-FTC and other randomized observational trials. was broken.

An observational study of 77,590 HIV-infected people in Spain found that TDF-FTC users had a nearly 50% reduction in the risk of COVID-19-related hospitalization. Another observational study conducted in 536,574 of her HIV patients found that TDF-FTC users had a 58% lower risk of COVID-19-related death compared with abacavir-zidovudine users. Reported. Some studies even found that TDF-FTC use lowered her risk of a COVID-19 diagnosis.

A phase II trial of TDF-FTC in 60 patients with mild COVID-19 in France found that the use of TDF-FTC significantly reduced nasopharyngeal shedding of SARS-CoV-2. I was. However, the drug has never transitioned to a phase III randomized trial for COVID-19 treatment in non-hospitalized patients.

Findings and conclusions

The TDF case study demonstrates that decision-making systems support the conduct of randomized trials of commercially viable drugs such as mornupiravir and remdesivir, but generic drugs such as TDF have limited commercial potential. has indicated that it does not support the implementation of

This case study also epitomizes a common mistrust and serious misunderstanding of observational studies. This is a weak justification, but an important determinant for not starting a randomized trial of TDF. Non-profit funders were disappointed by the inconsistent observational studies of hydroxychloroquine published in even several prominent medical journals, although they were later withdrawn. , dismissed their findings.

In addition, observational studies are subject to confounding bias. However, all confounding concerns should be contextualized. The researchers steered the HIV patient to her TDF or other drugs while carefully controlling for all confounding factors. Also, the measured confounding was not significant as the adjusted and unadjusted estimates were comparable.

Therefore, observational studies of TDF and severe COVID-19 in HIV patients have not been randomized, thus inappropriately suggesting a strong association between TDF and a lower risk of severe COVID-19. I didn’t get it.

Therefore, completely ignoring observational studies is inappropriate. Instead, observational evidence should be considered, especially if the evidence points to strong associations and, where appropriate, rationally exclude data, but only after considering alternative explanations. #

Indeed, the enormous investment of societal resources into randomized trials, including funding, volunteers, etc., requires incorporating all available evidence, including from observational studies, into reuse decisions. increase.

Based on these lessons learned from the TDF story during the first two years of the COVID-19 pandemic, researchers can guide decisions about drug repurposing of drugs with no commercial value for future public health emergencies. Suggested some recommendations to guide. First, public health agencies should maintain well-edited databases of electronic medical records to identify suitable drug diversion candidates.

Second, institutions should make these databases easily accessible to specialized data analysis groups or academic researchers who may rapidly develop appropriate drug repurposing assessments. Most importantly, decision makers need early consideration of observational evidence to expedite initiation of randomized trials.

Rapid action is paramount in the antiviral context. For example, anti-SARS-CoV-2 immunity is widespread and other therapies are established, making it impossible to test the feasibility of combining TDF and nirmatrelvir in 2023.