For PASTEUR Act advocates, the finish line is in sight for antibiotic development aid

Blue and clear capsules

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With the clock ticking on Congress to finish its business before the end of the year, groups representing infectious disease and public health professionals and the pharmaceutical industry are trying to push a bill across the finish line that could change the antibiotic development landscape.

The bill, known as the PASTEUR (Pioneering Antimicrobial Subscriptions to End Upsurging Resistance) Act, would create a subscription-style payment model in which the federal government would pay up front for access to Food and Drug Administration (FDA)-approved antibiotics that target drug-resistant pathogens and meet critical, unmet health needs.

The aim of the bill, which would delink companies' profits from the volume of antibiotics sold, is to help solve the market challenges that have led many pharmaceutical companies to abandon antibiotic development and contributed to the weak pipeline for new, innovative antibiotics.

Originally introduced in 2020 and re-introduced in June 2021, the PASTEUR Act, according to advocates, is closer than ever to becoming a reality in the wake of the COVID-19 pandemic and amid growing concern about rising antimicrobial resistance (AMR) rates and the lack of new antibiotics. But time is running out, and the how the bill might fare in the next Congress is unclear.

"I've never seen the level of excitement over an AMR bill that I've seen with the PASTEUR Act," Amanda Jezek, senior vice president of public policy and government relations at the Infectious Diseases Society of America (IDSA), told CIDRAP News. "There's been a lot of momentum and now we're just waiting for that right moment for Congress to actually pull the strings and move things forward."

Market challenges and the thin antibiotic pipeline

Antibiotics are one of the wonders, and the underpinnings, of modern medicine. Without them, minor infections could have severe consequences, and joint-replacement surgery, organ transplants, chemotherapy, even childbirth, would be more dangerous.

But bacteria have defense mechanisms against antibiotics, and those mechanisms have been multiplying ever since the discovery of penicillin. An increasing number of bacterial infections are resistant to multiple classes of antibiotics.

There's been a lot of momentum and now we're just waiting for that right moment for Congress to actually pull the strings and move things forward.

Amanda Jezek, IDSA

The public health implications of AMR have been known for years, but the number of people affected is just beginning to come into focus. A study published earlier this year in The Lancet estimated that 4.95 million deaths in 2019 were associated with AMR, including 1.27 million that were directly attributable to a drug-resistant infection. And data from the Centers for Disease Control and Prevention (CDC) show that US hospitals saw a 15% increase in infections and deaths from drug-resistant, hospital-acquired bacteria in 2020.

"More and more patients are being impacted by antibiotic resistance, and physicians do not have the tools they need to help take care of those patients," Jezek said.

While the public health value of antibiotics is unquestionable, they are not as profitable as other drugs. Unlike many other medications, antibiotics are used only for a limited time. And to prevent the development of resistance, new antibiotics are used sparingly and reserved mainly for infections that are resistant to older drugs. As a result, new antibiotics don't produce sufficient revenue for the companies that develop them.

This has led many large pharmaceutical companies to abandon antibiotic development altogether in favor of more lucrative drugs. And while there many small biotech companies that are developing innovative new antibiotics, research and development is costly. Discovering and developing a new antibiotic and successfully getting it through clinical trials and regulatory approval can cost well over $1 billion.

In recent years, groups like the Biomedical Advanced Research and Development Authority (BARDA) and the Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) have emerged to provide financial "push" incentives that provide early-stage funding help cover some of the costs of developing of new antibiotics. This funding has been critical for getting antibacterial products into and through expensive clinical trials.

But with the limited return on investment from antibiotics, smaller companies struggle to survive even when they get new products approved by the FDA. According to a report earlier this year from the Biotechnology Innovation Organization, of the 12 antibiotics companies that have gone public over the last decade, only 5 are still active today.

These economic challenges have, in turn, led to a relatively thin pipeline of new antibiotics. According to the most recent World Health Organization (WHO) analysis, there are only 27 new antibiotics in development against the bacteria that the agency has deemed "priority" pathogens because of their resistance to current antibiotics and their ability to cause severe infections. Altogether, there are 77 antibacterial agents in clinical development.

gloved hand with petri dishes in lab

In contrast, in 2020 there were more than 1,300 drugs medicine and vaccines in development for various cancers, according to an analysis by the industry lobbying group PhRMA.

A 'Netflix-style' model

That's the dilemma that advocates hope the PASTEUR Act could help solve. The bipartisan legislation, reintroduced in June 2021 by Sen. Michael Bennet (D-Colo.), Sen. Todd Young (R-Ind.), Rep. Mike Doyle (D-Pa.), and Rep. Drew Ferguson (R-Ga.), would authorize the Department of Health and Human Services (HHS) to enter into subscription contracts with companies that develop a "critically-needed antimicrobial" that targets infections identified by a congressionally appointed body of experts.

Under the contracts, the government would pay pharmaceutical companies anywhere from $750 million to $3 billion up front for patients covered by federal insurance programs (such as Medicare, Medicaid, and the Veterans Health Administration) to have access to a new antibiotic for 5 to 10 years. The bill would also establish a grant program under the CDC to support appropriate use of the antibiotics in hospitals.

Dubbed by some a "Netflix-style" model, the idea is similar to a program that's under way in the United Kingdom, where the National Health Service has agreed to pay up to £10 million ($12.4 million US) a year for up to 10 years for access to the antibiotics cefiderocol and ceftazidime-avibactam, manufactured by Shionogi and Pfizer, respectively. UK policymakers hope that paying an annual fee to drugmakers for new antibiotics will ease concerns about the return on investment and incentivize other companies to pursue antibiotic development.

David Hyun, MD, director of the Antibiotic Resistance Project at the Pew Charitable Trusts, says that a "pull" incentive that provides set funding based on the public health value of a new antibiotic, rather than on sales volume, will help provide a more stable return on investment for companies that develop new antibiotics.

"We view the PASTEUR Act as a really integral and essential component of the battle against antibiotic-resistant infections," Hyun said. "It's going to go a long way toward fixing the stagnant antibiotic development pipeline."

Pew and IDSA were among 165 organizations that recently sent a letter to congressional leaders calling on them to pass the PASTEUR Act.

"Novel antimicrobials must be used judiciously to limit the development of resistance, so payment based on volume fails to drive innovation," the letter stated. "PASTEUR's subscription model is an innovative way to pay for novel antimicrobials that will revitalize the pipeline and support appropriate use."

We view the PASTEUR Act as a really integral and essential component of the battle against antibiotic-resistant infections. It's going to go a long way toward fixing the stagnant antibiotic development pipeline.

David Hyun, MD, Pew Charitable Trusts

Critics challenge premise of the bill

But not everyone believes the PASTEUR Act is the right answer.

In another letter sent to Congress in November, a coalition of academics, clinicians, and advocacy groups argued that the premise of the bill is "fatally flawed" because new antibiotics are not required in clinical trials to show they are more effective than current antibiotics or that they improve patient outcomes. Phase 3 trials typically aim to demonstrate that new antibiotics are noninferior to the standard antibiotic treatment.

The letter also argued that clinical trials for new antibiotics should include patients with infections that are resistant to current antibiotics, and that the legislation doesn't include the antibiotic stewardship measures needed to prevent the development of future resistance.

"The PASTEUR Act would award billions in federal funding to pharmaceutical companies for newly developed antimicrobials as a financial incentive," the coalition wrote. "However, it does not address the overarching problem that recent antimicrobials approved by the FDA have not been proven to work against resistant infections or are not more beneficial than other available and less expensive alternative treatments."

Neil Clancy, MD, an infectious disease physician at the University of Pittsburgh and the VA Pittsburgh Healthcare System who is a supporter of the bill, called the arguments in the letter a "gross oversimplification."

"It doesn't reflect how antibiotic development works or how antibiotics get approved or used in the marketplace," Clancy said, noting that several antibiotics that have been approved in recent years after showing noninferiority have ultimately proven to be superior to the standard therapy. "They've saved lives, improved outcomes. This idea that the only way you get drugs of value into the clinic is through a superiority trial has been disproved over the past decade."

Clancy also said there are a lot of ways that a new antibiotic may offer value and advantages to patients that aren't measured in clinical trials.

"Maybe it's less toxic, or helps people get out of the hospital quicker. Maybe it's just easier to administer. Maybe it can be given orally or is dosed less frequently," Clancy said. "These are all outcomes of benefit in the real world that historically have not been considered in definitions of superiority."

This idea that the only way you get drugs of value into the clinic is through a superiority trial has been disproved over the past decade.

Neil Clancy, MD, University of Pittsburgh

In addition, Clancy and others note that including patients with resistant infections in randomized clinical trials raises practical and ethical challenges.

"Ethically, people with life-threatening infections must be given the best available treatments," IDSA president and professor of infectious diseases at Emory University School of Medicine Carlos del Rio, MD, wrote recently in Stat News. "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."

Hyun said that the very premise of the bill—delinking antibiotic revenue from sales volume—supports antibiotic stewardship, because it will remove the pressure for the companies to push for more use of the new drug. And he said the bill contains guardrails to ensure that the new antibiotics that might be eligible for subscription contracts are truly needed.

"There's a review process outlined in the bill that puts the onus on the HHS secretary to develop an external advisory committee made up of infectious disease doctors and pharmacists and public health experts so that they can actually evaluate the candidate antibiotic that's being put forth to see if it's really filling an unmet need when it comes to antibiotic-resistant infections," he said.

US Capitol building
Elliott P. / Flickr cc

Hyun and Jezek said the PASTEUR Act also contains much-needed funding for antibiotic stewardship programs in US hospitals, with priority given to small, rural, and critical hospitals that have not had the resources to develop robust antibiotic stewardship programs.

Other critics include Brad Spellberg, MD, chief medical officer at the Los Angeles County-University of Southern California Medical Center and a longtime advocate for building a sustainable antibiotic development pipeline. Spellberg's concern is that a pull incentive like that offered in the PASTEUR Act, on top of push incentives from groups like CARB-X and BARDA, will result in a glut of antibiotics that aren't much better than what's currently available.

"Sadly, most of what industry has chosen to bring to market after having all of these new incentives in place has been me-too drugs that don't address unmet need, and yet they have priced these drugs at outrageous levels," Spellberg said in an email. "Then they complain that more incentives are needed because some of the companies that have brought these drugs to market have gone out of business."

Spellberg calls the bill a clever maneuver by the pharmaceutical industry to turn the subscription model around and get the government to pay them money for drugs that will rarely be used. He also says AMR is a not "moonshot" problem that can be solved by the federal government throwing money at pharmaceutical companies.

Because resistance is a perpetual problem, Spellberg says what's needed is an independent board that would establish and regularly update an official list that restricts the pathogens that can be targeted for public incentives. He believes this approach would spread out approvals for new antibiotics over time, limit the use of public money for antibiotics that don't address unmet need, allow academic labs and nonprofits to play a greater role in antibiotic development, and reduce the reliance on for-profit companies.

"What we need instead of a big cash giveaway is a far more thoughtful, slow, deliberative process that results in a slow, steady drip of new drugs every few years in perpetuity," he said.

What we need instead of a big cash giveaway is a far more thoughtful, slow, deliberative process that results in a slow, steady drip of new drugs every few years in perpetuity.

Brad Spellberg, MD, University of Southern California

For his part, Clancy says that while some of the new antibiotics that will emerge if the PASTEUR Act gets passed may have some redundancy, that's okay.

"Our objective here is to have a viable pipeline where we're producing a certain number of these drugs—a number of which will have overlapping spectra and utility—so that we have treatment options," he said. "And moreover, as resistance emerges to the new drugs, as inevitably will happen, we'll have agents on the shelf that can be used."

The next steps

For now, though, the question is whether the PASTEUR Act will get passed before the end of the year. And although there is momentum, that's not a certainty.

Some recent changes have been made to the bill by its sponsors to help make it easier to pass. Notably, the amount of money to fund the subscription contracts was cut from $11 billion to $6 billion, Jezek explained, as part of efforts to add the PASTEUR Act as an amendment to the National Defense Authorization Act (NDAA), one of two annual pieces of legislation that specify the budget and expenditures for the Department of Defense.

"We had heard that $11 billion was just going to be too big a lift in Congress," Jezek said. But she and Hyun both feel that $6 billion is enough to give the subscription model program a meaningful jumpstart.

"The significance of this bill is to really kick-start this new pull incentive mechanism and put it into place," Hyun said.

There are other options if PASTEUR doesn't make it into the NDAA. Jezek said it could also get added to an omnibus appropriations bill that would fund the government for next year.

"We want to get PASTEUR done any which way we can, by any vehicle that is feasible," she said.  

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