New COVID Drugs Face Delays as Trials Get Harder to Do

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After two years of breakneck research, scientists have amassed a collection of therapies to treat people with COVID-19. Researchers fear that the clinical trials required to test these new treatments will become more difficult, and that this could lead to the development of less effective treatments.

Vaccinations have resulted in a decrease in severe diseases in many areas, which has reduced the number of potential participants to study. The number of effective treatments is increasing the hesitance to sign up for trials. This makes statistical analysis more difficult.

” It was easier to do research in past times. Now, you have to design a study that meets both the standards of care doctors and patients desire. It’s much harder,” Elizabeth Hohmann, a Massachusetts General Hospital infectious-disease expert, says.

Doctors treating people with COVID-19 can choose from roughly half a dozen types of therapy that have been recommended by the World Health Organization, or by national authorities such as the US Food and Drug Administration (see ‘Virus-taming tools’). There are antiviral tablets, synthetic antibodies, and steroids. Some reduce the chance of death for patients already in hospital. Others reduce the likelihood of being hospitalized at all. Death rates are dropping in some countries that are fortunate enough to have access to these treatments, and modelling suggests that widespread antiviral treatment could prevent the majority of COVID-19 deaths.

Source: World Health Organization, US National Institutes of Health. Credit: Nature

However, many areas have limited access to affordable therapies. There’s also the looming spectre of resistance to drugs such as the antiviral Paxlovid (nirmatrelvir-ritonavir), developed by Pfizer in New York City. Researchers fear that the pace of developing new treatments will slow down, leaving many people in need.

Shrinking pool

Certain countries that have been hard hit have seen their death rates drop dramatically, largely due to vaccines. In Brazil, for example, where deaths were once running at 3,000 deaths a day, the figure has declined to less than 200 a day. Despite this good news, trials can be complicated.

At the beginning of the pandemic, health researcher Edward Mills at McMaster University in Hamilton, Canada, and his colleagues set up a trial in Brazil to learn whether existing drugs could prevent the most serious outcomes of COVID-19. When they launched the trial, called TOGETHER, in early 2020, the share of study participants who eventually died or had to be hospitalized was 16%. After vaccines became available, the number of participants who died or had to be hospitalized dropped to 3-5%. The organizers had to enroll more people in order to test whether certain drugs could prevent severe outcomes. This meant that they had to expand the trial to other locations in South Africa, Pakistan and the Democratic Republic of the Congo.

Another type of hesitancy

Scientists are also concerned that even those who are eligible for trials are less likely to participate than they were at the start of the pandemic.

When Hohmann began overseeing a trial called ACTT to test COVID-19 treatments in early 2020, recruitment was quick: ill people had no better option. By April 2020, the trial had enrolled 1,062 people. And by the end of 2020, it had shown that the antiviral drug remdesivir speeds recovery and prevents death.

But Hohmann states that as more effective treatments like remdesivir became accessible, it became harder to recruit participants for future trials. Many people feel safer sticking with the established regimen, which today includes both remdesivir and the steroid dexamethasone, than trying an experimental drug as well.

” It takes a more adventurous person to take up that third drug,” Hohmann states. Hohmann said that it takes civic-mindedness to sign up to a trial even if your life isn’t at risk. She also suspects that the stress and turmoil of the pandemic have eroded potential participants’ altruism.

Hesitance of another sort might have affected a Canadian clinical trial for the drug losartan as a treatment for severe COVID-19. The majority of people in Canada became vaccinated during 2021, so most of the people available to join the losartan trial were unvaccinated. That could explain the rise in the share of people who were invited to join the study but declined: 18% in mid-2021 and 35% by the end of the year. Trial organizers suspect that the same factors that make people hesitant to receive vaccines, such as distrust of mainstream medicine, also make them disinclined to take experimental drugs.

Statistical complexity

As the number of treatments has increased, so has the complexity and accuracy of the statistical calculations required to determine if a new drug is safe and effective. Researchers might need to recruit more participants for trials, which can take longer.

This is exactly what the PRINCIPLE trial organizers have seen. The trial tests whether repurposed drugs can speed up recovery or keep infected UK residents away from the hospital. All participants in the study receive the current standard care. This means that doctors can prescribe additional treatments. This reduces any differences in outcome between participants who received the placebo and those who received the treatment under study, according to Ly-Mee Yu (a medical statistician at Oxford, UK) and PRINCIPLE’s lead statistician. Because of the smaller differences, researchers have to work with larger numbers of participants. Therefore, trials take longer.

Hohmann notes that if researchers want to compare a new, highly effective drug against Paxlovid, the powerful antiviral that is now the leading treatment for early COVID-19, they will need to recruit a huge number of trial participants to discern a statistically significant difference between the two treatments. She says that Paxlovid would be a “game changer” to defeat.

But researchers may need to accept the difficulties of finding a Paxlovid-resistant strain. Recent experiments on cells 4,5 have shown that Paxlovid resistant strains of virus might emerge. This is a stark reminder of how the virus rules the game, no matter how complicated it may seem.

This article is reproduced with permission and was first published on June 13 2022.


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