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New Study Provides Insights into Potential Regulatory Treatment of COVID-19 Drugs

By Beatrice Brown

As the global pandemic continues, trials have been established to test whether existing drugs such as hydroxychloroquine could be repurposed to treat patients with COVID-19. There are also hopes that a novel drug will surface. But questions remain about when treatments and vaccines will become available.

There is currently great optimism that a treatment or vaccine will be developed quickly, but there is no assurance that such a vaccine or treatment will be highly effective or that normalcy will return in any particular timeframe. A recent study published in the Lancet ID by Jonathan J. Darrow, Mehdi Najafzadeh, Kristina Stefanini, and Aaron S. Kesselheim provides data that might help to temper enthusiasm with evidence.

This new study evaluates the FDA’s regulatory flexibilities and provides critical insights as to how new COVID-19 treatments are likely to be reviewed by the FDA.

As explained in the Lancet ID study, there are several expedited programs that give the FDA flexibility in its approval process of both new drugs and new indications for existing drugs, including the Orphan Drug Act program, the Fast Track program, the Accelerated Approval program, the Breakthrough Therapy program, and the Priority Review program.

A key finding by Darrow et al. is that the FDA has demonstrated flexibility in its approach to antimicrobial drugs. The authors explain: “Since 2012, the FDA has promulgated antimicrobial-specific guidance documents that reiterate the FDA’s ongoing commitment to regulatory flexibility for this important class of drugs.” Antimicrobial products have  experienced shorter total clinical development and FDA review times, on average, than non-antimicrobial drugs.

Antivirals make up a subclass of antimicrobials, and COVID-19 is caused by a virus. It is therefore likely that these expedited approval programs will be used to help accelerate access to a COVID-19 treatment. The study by Darrow et al. found that 91% of antivirals between 1984 and 2018 used one or more of these expedited programs.

Even with expedited development and approval, however, new drugs can take several years to reach the market. According to the study, median clinical development time for antivirals was 4.2 years and median FDA review time was 0.6 years. However, these figures are based on approved treatments.

But many drugs that initially appear promising fail to ultimately demonstrate benefit or have safety problems. Considering this, it is possible that it could take longer than the average figures cited above before an approved treatment for COVID-19 is available. On the other hand, drugs such as remdesivir have already been under study for several years, potentially shortening the remaining approval timeline if the drug is ultimately shown to be safe and effective. Unprecedented resources have also been deployed to accelerate timelines, potentially leading to faster than average development and approval.

Still, the public should understand that it may be some time before a suitable COVID-19 therapy or vaccine is discovered and approved. Until then, it will remain important to follow the advice of public health officials to engage in measures such as physical distancing, frequent handwashing, and mask wearing.

In addition, even if a treatment is rapidly approved, the need for continued research may not yet be over, because approval of a drug does not guarantee any particular level of effectiveness.

This concern materialized in the approval of the first drugs to treat HIV — an epidemic which helped spur the creation of several of the expedited development and approval programs that are still in use today. These early drugs were not particularly effective. In 1987, the FDA approved the first drug for the treatment of HIV, azidothymidine (AZT), but US death rates from HIV continued to increase rapidly until additional therapies were introduced beginning in 1995.

There is a need for the regulatory flexibilities described in the Lancet ID study, particularly in the context of infectious diseases, a therapeutic category for which treatments are often highly efficacious or even curative. And drugs approved via the FDA’s expedited pathways have been shown to provide greater incremental benefits (0.182 QALYs), on average, than non-expedited treatments (0.003 QALYs).

However, it is important to evaluate all treatments, whether expedited or non-expedited, on their merits.

When no approved treatments are available, any new treatment—no matter how small its benefit—is likely to qualify for expedited approval, including the FDA’s “breakthrough therapy” designation. When drugs offering small therapeutic benefits are granted expedited status with names such as this, there is a risk of unrealistic optimism.

We should take care to ensure that evidence standards are not lowered unless the potential for large therapeutic benefits is present. Although this may not always be clear, there is less urgency to rush the approval of drugs that are not likely to offer more than marginal benefit, particularly when harm is uncertain.

Pandemics like COVID-19 certainly require the prompt approval of treatments, but efficacy and safety should not come at the cost of speed.

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Beatrice Brown

Beatrice (Bea) Brown is a Research Assistant for the Program On Regulation, Therapeutics, and Law (PORTAL) within the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women's Hospital. She received her Master of Bioethics (MBE) from Harvard Medical School in 2020 and her BA in Ethics, Politics, & Economics from Yale University in 2019. During the 2019-2020 academic year, Bea was a Petrie-Flom Student Fellow and wrote a research paper proposing a new argument for a constitutional right to physician-assisted death by redefining what it means to heal.

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