Antibiotic development advocates and infectious disease experts have been warning for years that the pipeline for new antibiotics is thin and ill equipped to keep pace with the spread of antimicrobial resistance (AMR). They've published numerous reports and analyses in recent years to highlight the problem.
Now, a new report indicates that without additional investments in antibiotic research and development (R&D) from governments and other stakeholders, the pipeline for new antibiotics could become considerably weaker over the next decade, with only a few candidates in the late stages of development.
But the report, released yesterday by the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA), also suggests that a different future, one with a much stronger antibiotic pipeline, is possible if governments implement effective pull incentives to stimulate antibiotic R&D and attract more private investment.
"This analysis demonstrates why urgent action is needed if we are going to reinforce our pipeline of antibiotics and protect the world from rising drug resistance," James Anderson, MBA, IFPMA's executive director of global health, said in a press release.
New payment models needed for antibiotics
The analysis, based on modeling performed by IFPMA and disease forecasting company Airfinity, starts with a look at the current situation. It shows that from 2017 through 2023, only 10 new antibiotics or combinations were approved by regulatory agencies. Only two of these antibiotics are defined as innovative by the World Health Organization (WHO), and none constitute a new class of antibiotic.
Furthermore, only one antibiotic candidate in phase 3 trials addresses the four bacterial pathogens that the WHO has classified as critical-priority pathogens. Of the WHO's seven high-priority pathogens, only two have innovative drugs in development.
"There is consensus from the WHO and many other experts that the pipeline is not sufficient to meet the demands of increasing resistance in the priority pathogens," the report states.
The widely cited reason for the relative lack of new antibiotics is the inadequate return on investment for drug developers, which is driven by several factors. These include the limited time for which antibiotics are needed (typically a few weeks or months in the case of more severe infections), the small population of patients with highly drug-resistant infections, and the need to keep new antibiotics as reserve or last-resort options.
In addition, recent research has found that clinicians are still opting for older, generic antibiotics to treat resistant infections, even when they have access to newer antibiotics.
This analysis demonstrates why urgent action is needed if we are going to reinforce our pipeline of antibiotics and protect the world from rising drug resistance.
The lack of economic incentive has led many large pharmaceutical companies to abandon antibiotic development for more lucrative drug-development efforts. While smaller biotechnology companies are trying to pick up the slack, several have gone bankrupt even after having an antibiotic approved. And many scientists who've been focused on antibiotic R&D are leaving the field, raising concerns about who is going to discover the antibiotics of the future.
"You can't access a drug that doesn't exist because nobody wants to make it," Amanda Jezek, senior vice president of public policy and government for the Infectious Diseases Society of America, said at an event for the launch of the report.
To date, only one country—the United Kingdom—has implemented a pull incentive to try and solve this problem. Using a subscription-style payment model, the National Health Service is paying pharmaceutical companies a yearly fee for access to two antibiotics—cefiderocol and ceftazidime-avibactam—that can treat severe, multidrug-resistant infections.
The idea behind this alternative payment model is that providing antibiotic developers with a predictable stream of revenue based on the public health value of their products, rather than reimbursing them based on the quantity of drugs sold, will incentivize companies to continue antibiotic R&D efforts while also promoting appropriate antibiotic use. Advocates also hope these incentives will bring more private investment to the table.
Canada is exploring a similar model, and Japan has piloted its own antibiotic revenue guarantee. A bill that would create antibiotic subscription payments in the United States (the PASTEUR Act) has been in Congress for several years and has bipartisan support but is yet to receive a vote.
But IFPMA and other groups that have been advocating for governments to provide push and pull incentives for early- and late-stage antibiotic development say more countries need to get on board to make a difference. They are hoping that the upcoming United Nations (UN) High-Level Meeting on AMR in September will provide a spark.
"There is broad consensus across non-profit and for-profit companies and think tanks on the importance of implementing push and pull incentives as quickly as possible," said Damiano de Felice, PhD, director of development and external engagement for CARB-X (Combating Antibiotic-Resistant Bacteria Biopharmaceutical Accelerator). "The time to act is now."
Two scenarios
But in the first scenario modeled in the report, there have been no new efforts to implement these types of economic pull incentives. As a result, the model predicts the pipeline for new antibiotics would continue to deteriorate from 2026 onwards as existing funding for late-stage antibiotic studies dries up. By 2033, there would be 8 new antibiotics approved, only 26 new antibiotic candidates in the pipeline, and only 6 candidates in late-stage development.
The second scenario assumes that more countries implement UK-style pull incentives starting in 2025 and that those incentives in turn attract more private investment for antibiotic R&D. Under that scenario, the model predicts 19 new antibiotics approved by 2033, 72 candidates in the pipeline, and 41 in the late stages of development.
Additional modeling on the expected impact on disability-adjusted life years (DALYs) from four WHO critical-priority pathogens found that, under scenario one, DALYs would increase by an average of 35% in high-income countries (HICs) by 2033. Under scenario two, the DALY burden would decline by 50%. Although the impact was modeled only for HICs due to data and model limitations, the authors say similar benefits could be expected globally.
"Robust pull incentives are crucial in encouraging the research and development investment needed, and by demonstrating the impact that these can have, this report underscores the economic and health imperative for governments to act boldly in a year when the UN is focused on combatting AMR," Anderson said.
