A panel of experts in human and veterinary medicine charged with advising the US government on antibiotic resistance has come up with a set of recommendations to boost development of vaccines, diagnostics, and new therapies that could reduce the spread of antimicrobial resistance (AMR) in humans and animals.
In a draft report that emerged from last week's meeting of the Presidential Advisory Council on Combating Antibiotic Resistant Bacteria (PACCARB), the panel identified the critical issues that hinder development of vaccines, diagnostics, and therapeutics and proposed recommendations to address those challenges.
The group's recommendations focus on encouraging additional public and private funding for research and development, creating new market incentives to encourage pharmaceutical and biotech companies to develop these products, easing regulatory pathways, and educating patients, clinicians, and veterinarians about the potential of these products to minimize and contain AMR in human and animals.
PACCARB was established in 2014 to provide input and policy recommendations to the Department of Health and Human Services on federal programs aimed at combating AMR.
Economic, regulatory barriers
A major focus of the report are the economic barriers that have hampered development of new products to combat antibiotic resistance, barriers that include high development costs, inadequate reimbursement, and an expensive, complex regulatory process.
"On average, the cost of development of a human vaccine or therapeutic ranges from $300 million to more than $1 billion and can take more than 12 years from the start of basic research to delivery to the consumer," the council writes. "A variety of financial and regulatory incentives are needed to address the lack of development of products and undervaluation of existing products to combat antibiotic resistance. Therefore, investment from both public and private entities is required to fill this gap."
Vaccines can address AMR in two ways, either by directly targeting bacterial pathogens that would require antibiotics or by targeting viral pathogens and reducing the likelihood of secondary bacterial infections. But, the council notes, the value of vaccines with respect to AMR is underappreciated.
To properly position vaccines as a component of the response to AMR, the council recommends more data to demonstrate the public health value of new vaccines with respect to AMR, and an expanded range of financial incentives to encourage pharmaceutical companies to focus research and development in this area. The council also recommends more communication from regulatory agencies so that vaccine developers understand what kind of data are needed for the review process.
Diagnostics, which can guide appropriate antibiotic prescribing and reduce the length of hospital stays by identifying levels of drug susceptibility or distinguishing between viral and bacterial infections, face similar challenges. "The cost of development, lack of clinical implementation of approved tests, inadequate reimbursement, and an expensive and complex regulatory process pose barriers to development," the council writes.
To encourage development of new diagnostics tests, the council recommends that a portion of funding for the development of new antibiotics should be dedicated to the production of a concomitant rapid antibiotic susceptibility test for that drug. They also call for sustained investment in funding mechanisms for developing new, cost-effective diagnostic tests, and more clinical and economic outcome studies to assess the clinical utility and cost-effectiveness of these tests.
The council also acknowledges that patient and clinician behavior also impedes greater investment in vaccines, diagnostics, and new antibiotics. For example, while clinicians and the general public are well-versed in the public health impact of children's vaccines, they know less about how adult vaccines can reduce the incidence of syndromes that lead to inappropriate antibiotic use. As a result, there's limited demand for these vaccines.
Similarly, limited use of antibiotic susceptibility tests and bacterial/viral diagnostic tests is a disincentive for diagnostics companies. The council suggests that greater patient and clinician education, along with evidence-based research, could help change this behavior and stimulate demand for these products.
To introduce more predictable and sufficient return-on-investment for developers of new antibiotics, the council recommends a mix of push and pull incentives.
The recommendations include strengthening funding for the government agencies and public-private partnerships currently providing financial and technical support for new antibiotic research and development—including the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X), the Biomedical Advanced Research and Development Authority (BARDA), the National Institutes of Health (NIH), and the National Institute of Allergy and Infectious Diseases (NIAID)—along with development of a model that delinks reimbursement for new antibiotics from sales volume. The panel also recommends that any incentives incorporate and support antibiotic stewardship.
Reducing AMR in animals
The report, which was divided into sections on human and animal health, takes a One Health approach to the AMR problem, acknowledging that solutions must address the spread of drug-resistant bacteria in human, animals, and the environment. "As recognized by many, AMR epitomizes the concept of One Health, as the genes that confer resistance to antibiotics; the organisms harboring these genes; and the pressures that enhance the evolution, spread, and persistence of these genes and organisms are present in all domains," the council writes in the report.
As in human health, the council views vaccines as part of the answer to reducing drug resistance, not only by preventing diseases that require antibiotics for prevention, but also by targeting zoonotic bacteria that can be carried by healthy animals but cause disease in humans, such as Salmonella and Campylobacter. Reducing human illness caused by these bacteria would reduce antibiotic use in human medicine. Similarly, the report calls for more research into diagnostics and alternatives to antibiotics.
"Given the need for innovation to minimize and contain antibiotic-resistant bacteria before they enter the food chain, the time is right to stimulate the development of novel approaches that will reduce the need for antibiotic use in food animals as well as make therapeutic uses more strategic and effective," the council writes.
The council's recommendations for animal health are less specific, due in part to the fact that there's been far less funding for research on antibiotic resistance in animals and how the use of vaccines, diagnostics, and alternatives to antibiotics in food animals could help reduce AMR while keeping animal populations healthy. In addition, the council acknowledges that veterinary medicine is more diverse than human medicine, having to cover a wide variety of animal species and their associated pathogens.
To that end, the council's main recommendation is drafting of a National Policy on Innovation for Food Animal Disease Interventions. This document would serve as the charter for the proposed Innovation Institute, a body within the US Department of Agriculture in which researchers, food animal production companies, startup companies, and universities could access the resources to advance new animal health products.
The proposed Innovation Institute would provide funding and technical support for research into how the vaccines and diagnostics could reduce bacterial disease in food animals cost effectively, along with research into antibiotic alternatives for treating sick animals.
September 2017 PACCARB draft report