Better Antibiotic Trials Sought as Congress Weighs Funding Bill

The FDA should implement more rigorous clinical trial standards for new antibiotics, doctors and infectious disease policy analysts say, as Congress considers legislation to fund antimicrobial development.

The Pioneering Antimicrobial Subscriptions to End Upsurging Resistance, or PASTEUR, Act would allocate $6 billion for the government to pay developers upfront for access to new antibiotics to treat drug-resistant infections. Lawmakers behind the bill, which is being pursued as an amendment to the National Defense Authorization Act, say it would help bring a wave of new treatments to patients and offer a much-needed response to the growth of infections resistant to the world’s existing supply of antibiotics.

But doctors and researchers warn that the industry-backed legislation and other projects pooling investments for drug development won’t be enough to ensure patients will get higher-quality treatments to fight drug-resistant infections, which could cause an estimated 10 million deaths per year globally by 2050.

The high rate of antibiotics withdrawn from the market over the past few decades due to efficacy concerns and low uptake is a sign that the Food and Drug Administration should require that new antibiotics are more beneficial than existing treatments, policy analysts say. Clinical trials should also be representative of the population most likely to benefit from the drug, they say.

“The solution to the problem” offered by the PASTEUR Act “is just sort of throwing money at a solution that hasn’t worked,” said John H. Powers III, former lead medical officer for antimicrobial drug development and resistance initiatives at the FDA.

“What we really need is to readdress this in another way,” added Powers, now a professor of clinical medicine at the George Washington University.

The Covid-19 pandemic brought renewed focus to antimicrobial resistance in the US and across the globe, prompting federal and local health departments to double down on efforts to expand programs to better track the use of antibiotics and antifungals and educate prescribers on the dangers of overuse.

The World Health Organization has identified antimicrobial resistance as “one of the top 10 global public health threats facing humanity,” and said in a June report that the current “development of new antibacterial treatments is inadequate to address the mounting threat of antibiotic resistance.”

The FDA said in an emailed statement that its actions “to encourage the development of new antibacterial drugs and strengthen the fragile antibacterial drug pipeline remain an important component of national and international efforts to combat antibiotic-resistant bacteria.”

It “remains committed to taking additional steps and further developing the scientific foundations to encourage the development of new antibacterial drugs and novel technologies as they are brought forth,” the agency added.

Subscription Model

Pharmaceutical companies typically get returns on investment based on the quantity of their products sold. But new antimicrobials are often used as final options when other treatment methods are ineffective, meaning they don’t offer the same opportunities for immediate returns on investment. Policy analysts say this limits new major investment in this space compared with more lucrative disease areas like oncology.

“The old model doesn’t work in the space because we don’t want to maximize the amount sold,” said Henry Skinner, CEO of the AMR Action Fund, which aims to help bring two to four new antimicrobials to patients within the next decade by pooling investments from several major drug companies, including Pfizer Inc., Eli Lilly & Co., and Johnson & Johnson.

He said that by holding new antimicrobials in reserve, “we prolong their utility and we reduce the amount of future resistance to these new drugs.”

Under the PASTEUR Act, the US government would establish a subscription model to “enter into contracts with the developers of novel therapeutics based on the value that the product would bring, rather than the volume that’s sold,” said Emily Wheeler, director of infectious disease policy at the Biotechnology Innovation Organization, a global trade group.

Health and Human Services Secretary Xavier Becerra supports the bill, saying in recent remarks that “the only thing we’re really missing with AMR is the money.”

The legislation is being pushed by Sens. Michael Bennet (D-Colo.) and Todd Young (R-Ind.), as well as Reps. Mike Doyle (D-Pa.) and Drew Ferguson (R-Ga.) in the House. A spokesperson for Young told Bloomberg Law that “every day that passes, we see more deaths on account of antimicrobial resistance, and this situation grows more challenging and more costly.”

A Flawed System

A spokesperson for Bennet told Bloomberg Law that the latest version of the PASTEUR Act “is updated based on feedback we received to ensure that the contracts are awarded to treatments that improve patient outcomes.”

But some doctors and policy analysts say the legislation won’t address issues with previously approved drugs, including the lack of clinical evidence among patients the drug is supposed to benefit and no requirement for new antibiotics to show they are dominant over existing treatments.

A 2020 study from Powers and other co-authors published in Mayo Clinic Proceedings found that 21 novel antibiotics approved from 1999 through 2018 included “at least one identifiable patient population that was explicitly excluded from enrolling in the supporting pivotal trials.”

“You look at some of these drugs and the labeling for the drug says the drug is for patients with limited or no options, when in fact, those people weren’t studied,” Powers said.

“What we’re left with then is a lack of evidence on how to use the drugs in practice or even if they are effective for the people who need them the most,” he added.

The FDA also accepts results from noninferiority trials as a basis for antimicrobial approval. In these trials, drugs are tested against a comparative drug or placebo to show that the treatment is either equivalent or not materially worse. The FDA said it allows these trials especially in situations where there’s an insufficient number of patients with a specific drug-resistant infection to carry out a clinical trial to demonstrate drug superiority.

But Reshma Ramachandran, a Yale School of Medicine family physician and the FDA task force chair for Doctors for America, said uncertainty around the level of benefit a new antibiotic has over a treatment with a longer history of safety and efficacy is “oftentimes why you don’t see clinicians or infectious disease doctors prescribing these new drugs.”

“The fact that drugs might be even slightly worse than existing drugs that we have out there doesn’t invoke a lot of confidence in terms of me as a clinician of using that drug if I already know there’s an alternative option that might be just as equivalent or even slightly better,” Ramachandran said.

Questions on the evidence being used to support FDA antibiotic approval has left treatments unsuccessful on the market long term. An analysis published in 2013 of FDA approvals of antibiotics and anti-infectives found that from 1980 to 2009, 43% of the 61 new molecular entity antibiotics approved during this period were eventually withdrawn from the market—higher than the 13% withdrawal rate among non-antibiotics.

A Needed Shift

Improved legislation or independent action by the FDA to revamp evidence development for new antibiotics is essential to deliver more effective treatments to patients unsuccessfully treated with first-line therapies, health policy analysts say.

The language in the PASTEUR Act or any other measures attempting to boost antibiotic development “should be explicit to say, ‘if you want this money, we’re looking at it for trials that had these characteristics,’” said Mark E. Miller, executive vice president of health care at the philanthropy-funded Arnold Ventures.

Ramachandran said the FDA also has the ability to take action now to ensure antibiotics in development meet more robust requirements for approval.

“The FDA itself could actually employ different guidance to change the requirements for regulatory approval for new antibiotics,” she said, though she noted this would “take a big effort from the agency” to issue recommendations and give the opportunity for public comment.

Powers said while subscription models for antibiotic drug investments could work, they should “be applied to products that actually meet the standard of improving patient outcomes by demonstrable evidence.”

“Right now there’s a disconnect in infectious diseases between how the studies are done, the evidence that we’re getting, and how those drugs might be used in practice,” he said.