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The Infectious Diseases Society of America (IDSA) is addressing the benefits and potential pitfalls of federal regulators’ emergency use authorizations (EUAs) for therapies during a pandemic – calling them “double edged swords.”
Furthermore, enrolling more high-risk people in COVID-19 clinical trials, reinforcing a message that monoclonal antibodies and other treatments can be useful but should not replace vaccination, and better preparation for future pandemics are among the highlights of new IDSA guidelines also released Wednesday.
Progress, policies, and procedures during the COVID-19 pandemic are commendable, but there is still room for improvement, IDSA experts said during a media briefing that coincided with publication.
“It’s absolutely necessary that we have timely and vital medications and vaccines available” during a pandemic,” Adarsh Bhimraj, MD, said during the briefing. However, by nature, EUAs feature “limited evidence that you have to act on.”
For example, when the US Food and Drug Administration (FDA) issued a therapeutic EUA for remdesivir, “the papers were not published and we were struggling as to how to use the medication,” said Bhimraj, chair of the IDSA COVID-19 Treatment and Management Guidelines expert panel and chief of the Neurologic Infectious Diseases Section at Cleveland Clinic, Cleveland, Ohio.
The EUAs “provide much needed therapies during pandemics, but when issued before sufficient evidence is available, may have unintended consequences,” the IDSA expert panel notes.
The reasons the FDA grants an EUA should be clear to providers, Bhimraj added. Unlike the clear criteria for vaccine EUAs, the benchmarks for therapeutic EUA are more opaque.
The expert panel reviewed each therapeutic EUA issued during the pandemic. In addition to remdesivir, they reviewed the benefits and drawbacks involved in EUAs for hydroxychloroquine, convalescent plasma, bamlanivimab, bamlanivimab/etesevimab, casirivimab/imdevimab, and baricitinib administered with remdesivir.
To improve the process, the FDA is considering expert input on EUAs going forward through an advisory committee, which Bhimraj said would be a “great step.”
Think of COVID-19 Therapies as Backup
Bhimraj emphasized that therapeutics for COVID-19 should be considered backup, not replacements, for vaccines. Monoclonal antibodies can be effective in high-risk individuals, for example, particularly if given early.
On the downside, they are labor- and time-intensive to administer because they are infusions.
The experimental antiviral molnupiravir (Merck), for which an EUA application was submitted last week, offers potentially more convenience as a pill, but the data so far is limited to 28 days.
The data “looks promising and the FDA is considering an EUA,” Bhimraj said. “There’s more data to come.”
“I hope that molnupiravir will deliver,” Rajesh Gandhi, MD, professor of Medicine at Harvard Medical School, Boston, Massachusetts, and an IDSA fellow, said during the briefing. He agreed that having treatment in pill form “will be much easier to deliver compared…to arranging an intravenous infusion or subcutaneous infusion.”
Both experts are looking forward to more data on molnupiravir. “I’m optimistic but skeptical until we see all the information from Merck,” Bhimraj added.
Room for Improvement
In the “lessons learned” paper, the IDSA panel identifies five major areas where improvements could be made. One example again refers to the EUA process and establishing minimal standards.
The remaining four areas where the IDSA believes action is needed target research protocols during COVID and future pandemics. They acknowledge the speed and breadth of investigations that have taken place over the past 18 months.
The panel also points to several well-conducted trials that addressed crucial clinical questions as examples of more robust research: the SOLIDARITY, RECOVERY, and ACTT-1 clinical trials.
In other instances, however, they note “serious shortcomings remain on trial conduct, dissemination and interpretation of study results, and regulatory support in pandemic settings.” In other words, there is room for improvement here as well.
The IDSA, for example, recommends establishing standardized criteria for COVID-19 clinical severity categories and outcomes for therapeutic trials. In a deadly pandemic, many trials used death as a measured outcome.
However, the panel notes some important subtleties can get lost. “Although mortality is an important overall outcome, intermediate clinical outcomes that capture the impact of treatments on clinical status are needed,” they write.
“This is especially important as few agents have shown mortality benefits and most trials were not designed to capture details of nonmortality outcomes.”
Another trouble spot are COVID-19 trials that look at combined outcomes, such as severe disease and death. This composite endpoint can make it more difficult to tease out the precise effects of treatment, they state.
Study Diverse Populations
Future trials also should enroll more diverse populations, the IDSA states. “We know that enrollment into clinical trials should reflect the population that’s most affected by the disease. This is one of our core principles,” Gandhi said.
“One thing that we must [improve upon] is to develop systems to facilitate and support the enrollment of people in the hardest-hit communities into research,” he said.
Underrepresented groups include ethnic and racial minorities, but future trials should also enroll more immunocompromised individuals, pregnant women, and children.
Pregnant women are at three times increased risk for severe COVID, Gandhi said, “and yet many of our treatment trials have had little or no enrollment of pregnant women. And finally children, even though children are less likely to get severely ill. It’s incredibly important to know how to treat children.”
The Need for Speed
A faster and standardized process for critical review of preprints and publications is likewise needed, the IDSA states.
“Due to the understandable urgency in disseminating data during the current pandemic, there has been a voluminous increase in fast-track publications, postings on preprint servers, and press releases without peer review,” the panel experts write.
“The trustworthiness of that evidence is questionable as it circumvents the usual safeguards of thorough peer review that ensures the scientific integrity of the evidence.”
The IDSA also calls for facilitating more research outside of US academic medical centers. Even in these traditional research settings, they note, the number of investigators, lab techs, and clinical research staff can be insufficient during a pandemic.
“While there are many barriers to doing so, completion of high-quality clinical trials during a pandemic can and must be accomplished,” the panel notes.
The IDSA updated its guidelines because, Bhimraj said, “we thought it was necessary to publish as a separate paper called ‘Lessons Learned from COVID-19 Therapies’ — not just to describe the shortcomings but also to use this as a ‘burning platform.’ “
The aim, he said, is “to suggest solutions, and, more importantly, stimulate a constructive dialogue among healthcare providers, lawmakers and the public to bring about a change in policy and preparedness — not just for the current ongoing panic, but future epidemics and emergencies.”
Quoting his own grandmother, Bhimraj said, “the time to dig a well is not when you’re thirsty.”
Bhimraj had no relevant financial relationships to disclose. Gandhi has served on a scientific advisory board for Gilead Sciences, Inc., serves on a scientific advisory board for Merck, and receives research funding from the NIH.
Damian McNamara is a staff journalist based in Miami. He covers a wide range of medical specialties, including infectious diseases, gastroenterology, and critical care. Follow Damian on Twitter: @MedReporter.
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