By 2050, drug-resistant infections caused by “superbugs” could kill 10 million people each year around the world. That’s more than the annual global death toll from cancer.
In new research published this year in The Lancet, drug-resistant infections were found to be at least partly responsible for nearly 5 million deaths worldwide in 2019. In comparison, Covid-19 — an emergency that prompted a global response unlike anything in recent history — killed at least 3 million people in 2020.
Policymakers have yet to confront the superbug crisis with anything like a Covid-level response. Researchers need to be developing many more, new antimicrobial drugs right now, but they are dangerously behind schedule.
The science is not the problem. From 2011 to 2020, the clinical success rate for a new antibiotic from Phase I to FDA approval was more than 16%, twice as high as the 7.9% industry average. It’s the marketplace — or rather, the lack of one.
Advanced new antibiotics and other antimicrobial agents must be used sparingly to prevent pathogens from developing resistance to them. This approach is medically sound. But it’s financially disastrous for drug makers, since new antimicrobials aren’t given often enough to generate the kind of revenue needed to recoup their development costs. Some of the most promising antimicrobials companies have gone out of business in recent years, even after successfully developing new treatments.
The Pioneering Antimicrobial Subscriptions To End Upsurging Resistance (PASTEUR) Act (H.R. 3932 and S.2076) that is currently before Congress would address this unique situation by allowing antimicrobial makers to enter into a subscription-like model with the federal government to ensure new antimicrobial medicines are available to address critical or hard-to-treat infections.
It’s similar to Netflix — subscribers can use as much or as little of the product as they need, rather than buying the medicine per dose. By paying antimicrobial makers a predetermined amount of money for the availability of their treatment, these companies don’t need to rely on the number of antimicrobial drugs sold to stay afloat financially. PASTEUR is a unique financing model that creates a reliable market for critically needed antimicrobials — and as a result, promises to ignite a desperately needed revitalization in antimicrobial development.
Unfortunately, a small number of physicians and public health professionals are placing the future of the PASTEUR Act in jeopardy. They’re calling on lawmakers to hold antibiotics to an unattainable standard — a superiority trial — to be eligible for a PASTEUR subscription contract. Specifically, they want developers to demonstrate new antimicrobials improve patient outcomes more than existing treatments. That’s different than the current standard for FDA approval, which dictates that clinical trials show that a new antimicrobial is at least as good as existing therapies.
Requiring pathogen-fighting drugs to outperform existing ones via superiority trials reflects a fundamental misunderstanding of how drug-resistant infections work and how clinical trials are conducted. It would actually undermine efforts to develop the antimicrobials sick people need for several reasons.
First, superiority trials for antimicrobials can put patients’ lives at risk. They also require a large number of participants.
Superiority trials need to prove that a new drug is more effective than the current standard for treatment. That differs from traditional clinical trials, or non-inferiority trials, which need to prove the new drug is just as effective as the standard treatment.
That seems simple enough. But for new antibiotics, the very patients who can demonstrate the trial antibiotic is superior to the existing treatment are patients with infections that aren’t responding to the existing treatment.
That creates major ethical concerns. Untreated or inadequately treated microbial infections can worsen within a few hours, creating an imminent risk of sepsis, an extreme and often deadly reaction to an infection. Ethically, people with life-threatening infections must be given the best available treatments. They can’t be enrolled in a double-blind clinical trial where they might end up in a control group that receives the existing treatment if their physician expects that the existing treatment won’t be effective against their infection.
Superiority trials could be ethically conducted when infections are completely resistant to all available therapies. But because such infections aren’t common, conducting clinical trials with only these patients would severely limit the ability to research new antimicrobials.
Second, superiority trials put the research community in pursuit of the wrong goal: a single best antibiotic. What’s needed are multiple new antibiotics and other antimicrobials to successfully treat a wide range of infections in diverse populations and keep ahead of superbugs as they evolve and develop resistance.
Third, traditional clinical trials are effective at delivering life-saving antimicrobials that are better than existing therapies. Daptomycin, dalbavancin, ceftazidime-avibactam, and ceftolozane-tazobactam — all essential antibiotics to treat multidrug-resistant infections — were approved through traditional trials that primarily enrolled people with non-resistant infections. Before these drugs were approved, extensive pre-clinical data demonstrated a high likelihood they would be superior to existing therapies, and clinical trials demonstrated they were as safe and effective as existing treatments. Post-approval data clearly showed these drugs were even superior in patients with life-threatening multidrug-resistant infections.
For treating HIV, many antiretroviral drugs have been approved based on their being non-inferior to available therapies. This non-inferiority approach is sound and well established.
There are better ways than superiority trials to collect data to demonstrate that new antimicrobials improve patient outcomes better than existing treatments. Overly prescriptive legislation will not deliver superior antimicrobials. Instead, that will come from leading NIH-funded scientists who are conducting research on how to measure the patient benefits of novel drugs in the context of ethical clinical trials, and biopharma companies that will bring new treatments to market. It will be continued investment in these approaches, the passage of the PASTEUR Act, and funding to support post-approval studies that will truly improve outcomes for people with serious infections.
The Infectious Diseases Society of America, which I lead, along with many other clinician and patient organizations, are calling on Congress to pass the act this year.
Waiting any longer would move the U.S. closer to the brink of a global health catastrophe. This is not the time to make the task of developing new antibiotics and fighting drug-resistant superbugs more difficult than it already is.
Carlos del Rio is an infectious disease physician, executive associate dean of Emory University at Grady Health System, a professor of medicine at Emory University School of Medicine, and president of the Infectious Diseases Society of America.
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