Congress, beware: False alarms are being raised to urgently authorize the transfer of billions in taxpayer funds by year’s end to pharmaceutical corporations under the guise of addressing the public health challenge of antimicrobial resistance.
The narrative behind this is now a well-used playbook: 1) start off with a story about a sick patient with a bacterial infection, 2) voice concern that existing antimicrobial treatments may not work, 3) point to the cause of having no effective options for treatment as being due to a lack of financial incentives for manufacturers to develop novel antimicrobials and 4) conclude that the solution to this problem is throwing money at it by demanding that Congress immediately pass the Pioneering Antimicrobial Subscriptions To End Up surging Resistance (PASTEUR) Act.
Under the PASTEUR Act, the federal government would award billions in the form of guaranteed revenues to drug manufacturers for individual antimicrobials as an inducement to continue drug development. However, glaringly absent from this seemingly perfect narrative is that these new antimicrobials gifted billions under the PASTEUR Act should be required to improve patient health outcomes to make clinical use or payment worthwhile.
For clinicians, U.S. Food and Drug Administration’s (FDA’s) approval signals that the approved treatment had been tested in clinical trials in participants like patients we would prescribe the drug to in practice. We’re also led to believe that with approval that there is “substantial evidence” of effectiveness that the drug works with limited risk of harm. However, for recently approved antimicrobials, this is not the case as these drugs are not studied in patients who have no options — yet FDA approves them as if they had.
FDA allows antimicrobial approvals based on trials that allow the new drug to be worse by some amount than older effective therapies, misleadingly framing this as “just as good as” current effective, less expensive treatments. Claiming this as a valid precedent for developing new drugs just because that’s the way it has been done does not help patients and does not qualify as “innovation.” The way the FDA has been approving these drugs needs to change to get better evidence for patients.
As a result, for those rare situations when physicians are faced with a patient who lacks effective therapy, they are left with, at best, costly treatment options of unclear benefit and at worst, antimicrobials that are less effective than what we have available. Using these new drugs is a shot in the dark due to the absence of evidence they are effective in patients who need them most. Instead, some drug manufacturers place the blame on doctors for not prescribing these drugs despite not demonstrating that they help our patients. Given the lack of valid evidence that new drugs improve the lives of patients with no options, clinicians are correctly skeptical. Clinicians treat patients, not test tubes, and drugs that look promising often fail when studied in critically ill patients.
This limited choice in antimicrobial therapies with improved effectiveness for those who need them most is by design due to persistent lobbying efforts by the pharmaceutical industry and their well-funded organizations. Over the past decade, legislation has passed which FDA has interpreted as allowing the agency to accept less and lower quality evidence as sufficient for approval. This loss in regulatory rigor has been coupled with other lucrative incentives including an additional five years of market exclusivity, further barring the introduction of less costly generics, and raising drug prices for unclear benefits to patients.
Consider for example plazomicin, the antibiotic used repeatedly to urge support of financial incentives such as the PASTEUR Act. Less than a year after the drug was approved by the FDA for the treatment of complicated urinary tract infections, its manufacturer announced bankruptcy. While the press refers to this as a tragedy, rarely mentioned is that plazomicin was approved based on a single trial with results showing it was not more effective in improving patient outcomes and potentially harmful, causing kidney damage more often than the older, less expensive drug to which it was compared. Unsurprisingly, the drug had poor sales.
Despite the company’s bankruptcy, plazomicin is still available to patients and clinicians sold by another manufacturer. Thus, the “tragedy” is the waste of resources on a potentially harmful drug for patients who already had options and with unclear effectiveness for others who lack options — not that the company filed for bankruptcy because they failed to provide evidence showing it was better for patients. While framed as “many” companies going bankrupt, only two — Achaogen and Melinta — with FDA-approved products have filed for bankruptcy. The second one was back in business within two years and received another approval for a drug that was not more effective than older drugs.
The typical business model for drugs where companies thrive on selling more may not work for antibiotics — the more you sell and the more patients use the drugs, especially in settings where they might not be needed, the more likely bacterial infections will develop resistance. Instead, new antimicrobials should be reserved for patients for whom there is evidence that the novel drugs work better for them. Such perceived limited profitability may also contribute to ongoing shortages of effective older antibiotics.
The federal government has taken steps to alleviate these concerns by allocating hundreds of millions in public funding to offset the costs of antimicrobial development through grants from the National Institutes of Health, Biomedical Advanced Research and Development Authority, the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator or CARB-X, and others. Under PASTEUR, taxpayers are being asked to pay on the back end too. However, whether PASTEUR would address or even worsen ongoing shortages remains unclear as it would only provide an incentive to keep new drugs available rather than older, less expensive antimicrobials.
PASTEUR would likely prevent drug companies like plazomicin’s manufacturer from going under through guaranteed returns for up to a decade. But without any strict requirement that the drugs should improve patient outcomes, this multi-billion-dollar gift would also lead to an influx of antimicrobials that we as physicians would have difficulty in determining whether they are beneficial or indeed harmful for our patients — exactly what we’ve seen in the last decade except with a higher price tag. When trials in patients with resistance are done, the results have not been as promised. For example, cefiderocol — touted as having a “new mechanism of action” and effective in test tubes against resistant bugs — was found in a clinical trial to result in 1 in 6 more deaths than older, cheaper drugs that themselves were believed to have suboptimal effectiveness in treating resistant infections.
PASTEUR would instead signal to drug companies that they can continue the same lackluster antimicrobial development — paid for in large part by the public already — divorced from improving patients’ health. What message does propping up failing companies send to others trying to develop drugs that do improve patient outcomes? Why bother? We’ve tried it this way for the last several decades and it’s not working — 15 new drugs for infections were approved between 2016-19 yet none of them were proven to improve patient outcomes and most cost more. We need better drugs, not just more drugs.
Congress should be looking further upstream to develop more appropriate incentives, requiring studies in patients who lack effective options, with outcomes directly measuring patient benefits such as improvement in survival, symptoms and daily function. This means putting the current FDA approval process of antimicrobials under scrutiny and moving away from ethically questionable trials that allow lesser effectiveness in patients with life-threatening diseases who already have effective options as a means for marketing approval. The current approval process leaves patients and their doctors in the dark about when new drugs if any should be prescribed. Instead, FDA should require more robust trials in a wider range of interventions demonstrating they are better at treating disease than available options.
The intent behind the PASTEUR Act may be laudable in attempting to move away from the typical business model of drug development of volume-based returns for drugs that need to be conserved today to ensure their benefit tomorrow. However, the bill fails to incentivize the most important consideration for doctors in prescribing any treatment to patients — that it should work to improve their health. Ignoring this critical aspect makes the PASTEUR Act just another blank check to drug manufacturers and further perpetuates the public health challenge of antimicrobial resistance and lack of effective therapies for patients who need them.
Reshma Ramachandran, MD, MPP, MHS is a family medicine physician and assistant professor at Yale School of Medicine. She co-directs the Yale Collaboration for Regulatory Rigor, Integrity, and Transparency (CRRIT). She also chairs the FDA Task Force for the independent, national non-profit organization, Doctors for America. John H. Powers, MD, FACP, FIDSA is an infectious disease physician and professor of Clinical Medicine at the George Washington University School of Medicine and adjunct professor at the University of Maryland School of Pharmacy.