Comments from The Pew Charitable Trusts re: Consultation on a draft global action plan to address antimicrobial resistance September 1, 2014 The Pew Charitable Trusts is an independent, nonprofit organization focused on implementing evidence-based policies to solve today s most challenging problems. Pew has been involved in the issue of antibiotic resistance for almost a decade, with efforts focused on implementing policies in the United States to address the urgent need for new antibiotics and the widespread inappropriate use of antibiotics in animal agriculture. We appreciate the opportunity to submit comments on the World Health Organization s draft global action plan to address antimicrobial resistance. Key Areas of Concern ( From the perspective of your organization, what are the most important areas of concern in AMR? ) Antimicrobial resistance, in particular bacterial resistance, poses a grave threat to global health and necessitates broad, multifaceted solutions. Pew focuses on three main areas: Incentivizing the Development of New Antibiotics and other Novel Therapies Ending the Overuse of Antibiotics in Food Animals Ensuring the Appropriate Use of Antibiotics across Healthcare Settings Incentivizing the Development of New Antibiotics and other Novel Therapies As the U.S. Centers for Disease Control and Prevention (CDC) identified in its 2013 threat assessment, antibiotic development is a critical component of any strategy to address antimicrobial resistance. 1 New antibiotics with novel mechanisms of action will always be needed, as the development of resistance to existing drugs inevitably develops. Antibiotic drug development has been in decline for decades, and the number of new drugs in the pipeline is alarmingly low. Pew analysis of the U.S. pipeline found 43 new antibiotics currently in clinical development as of June 2014; 2 however, given that, on average, no more than one in five drugs that make it to the initial phase of clinical trials receive U.S. Food and Drug Administration (FDA) approval, it is clear that there are too few drugs in development to meet current and anticipated patient needs. Moreover, many of the drugs currently in development represent known classes of antibiotics, and only a handful of therapies in early development target bacteria in a completely new way. Economic, regulatory, and scientific challenges all pose obstacles to antibiotic drug development. It is essential that governments and other stakeholders pursue policies to 1 Centers for Disease Control and Prevention, Antibiotic Resistance Threats to the United States, 2013, http://www.cdc.gov/drugresistance/threat-report-2013/pdf/ar-threats-2013-508.pdf. 2 The Pew Charitable Trusts, Antibiotics Currently in Clinical Development, June 30, 2014, http://www.pewtrusts.org/en/multimedia/data-visualizations/2014/antibiotics-currently-in-clinical-development.
encourage the development of antibiotics and ensure an adequately stocked pipeline that addresses current and anticipated patient needs. Ending the Overuse of Antibiotics in Food Animals Over 45 years of independent, peer-reviewed scientific studies have found a clear association between antibiotic consumption (in both people and food animals) and bacterial resistance. Additionally, the emergence of specific strains of antibiotic resistant bacteria in animals has been associated with the use of specific antibiotics. In some cases, those same strains have infected humans. The injudicious use of antibiotics in food animals presents a serious and growing threat to human health as the practice creates new strains of antibiotic-resistant bacteria. Drug companies, food producers, and veterinarians must take responsibility and assist in reduction efforts. Ensuring the Appropriate Use of Antibiotics across Healthcare Settings Appropriate antibiotic use across healthcare settings is needed to both slow the spread of resistance and protect individual patients from adverse effects associated with antibiotic use, such as Clostridium difficile infections and allergic reactions. In the United States, the CDC estimates that up to 50 percent of antibiotic use is either unnecessary or inappropriate. To curb inappropriate use in hospitals and outpatient settings, a broad range of stakeholders, including governments, public health experts, physicians and leaders of healthcare systems, must work together to implement evidence-based antibiotic stewardship programs. Current Work ( Is your organization currently involved in work related to AMR? If yes, how? ) Pew s work on antibiotic resistance began in 2008, when the Pew Commission on Industrial Farm Animal Production recommended, among other things, that the U.S. completely phase out the nontherapeutic use of antibiotics in food animals. Pew has worked to advance legislative, regulatory, and market-based solutions and to build public and policymaker awareness. Specifically, we supported the development of new the U.S. Food and Drug Administration (FDA) guidelines, issued December 2013, that will remove growth promotion in animals as an approved use for antibiotics. We have also collaborated with public health and consumer groups to bring about regulatory and policy changes on data collection and veterinary oversight of antibiotics. In addition, we have built public awareness of animal-use issues and have influenced institutional purchasing by universities, school districts and hospitals toward poultry and meat raised with responsible use of antibiotics. In support of drug development, Pew was actively involved in developing and advocating for the Generating Antibiotic Incentives Now (GAIN) Act, passed by the U.S. Congress in 2012, which addresses some of the economic challenges facing drug developers by offering an additional five years of market protection for certain antibiotics before they face generic competition. Pew is now working in partnership with congressional champions to support
legislation that would create a new limited population mechanism for approval of antibiotics for use in patients who have few other treatment options. In parallel, Pew is working to help identify, prioritize, and develop policy solutions to help address some of the scientific barriers to antibiotic discovery. Increasing awareness and understanding about AMR and of the actions and changes needed (Building Block 1) One key component of driving policy change will be raising the prominence of this issue at the highest levels of government. National strategies to combat antibiotic resistance, including national goals for reduction in antibiotic use in human and animal medicine, can help galvanize attention and resources and drive policy change. To be effective, national goals would require developing consensus among experts and key opinion leaders on the drivers of resistance in each key setting (inpatient, outpatient, and on the farm) and developing a shared understanding of what constitutes reasonable antibiotic use. In addition to developing expert consensus on underlying drivers of overuse and the potential for reductions, if informed by a wide-range of stakeholders, national reduction goals would help ensure that all actors engaged in antimicrobial resistance efforts are aware of the necessary actions and required resources and are better able to coordinate their activities. Additionally, the process of creating and announcing these reduction goals would increase the public s awareness of resistance and a greater understanding of the importance of the issue. Although additional surveillance is needed to ensure accurate assessment of these goals, experts can use currently available data to set and monitor improvement until better systems are in place. Optimizing the use of existing antimicrobials for human and animal health and in agriculture (Building Block 3) Reducing inappropriate antibiotic use in both human healthcare and animal agriculture is critical to slowing the development of resistance and preserving the usefulness of critically needed therapies. In hospital settings, formal antibiotic stewardship programs (ASPs) have been shown to be effective in better coordinating patient care and thereby reducing antibiotic usage. However, in the United States, despite the evidence backing these interventions, many hospitals have yet to implement programs of their own. Thus a key action in this setting is encouraging the adoption of ASPs. Public health authorities can aid in this effort through the provision of technical assistance. In the U.S., for example, the CDC recently released a Vital Signs report detailing key elements for hospitals to include an effective ASP. 3 Policymakers can also directly encourage uptake through state-level or national policies. A California state law requires all hospitals there to establish a process to monitor the 3 U.S. Centers for Disease Control and Prevention, Making Health Care Safer: Antibiotic Rx in Hospitals: Proceed with Caution, Vital Signs, March 2014, http://www.cdc.gov/vitalsigns/pdf/2014-03-vitalsigns.pdf.
judicious use of antibiotics in their facilities. 4 Additionally professional societies such as the Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America have called for federal policy efforts in the United States to mandate stewardship programs nationwide. 5 Most antibiotic use in humans, by sales, is in the outpatient setting. Research is needed to understand the contribution of outpatient prescribing to resistance and to develop policies, practices and an evidence base to reduce inappropriate use. Medical professional societies should also be actively engaged in stewardship efforts in these settings. The American Academy of Pediatrics (AAP) has demonstrated the important role these organizations can play in educating their members on antibiotic use and stewardship. Along with eliminating use of antibiotics for growth promotion in food animals, it is essential to develop production systems that do not rely on routine use of antibiotics for disease prevention or create conditions that lead to overuse of these drugs for therapeutic purposes. Achieving this goal will require a concerted effort on the part of agricultural interests, the veterinary community, regulators and policy makers. International efforts to develop standards and share best practices can be an important driver of change. In order to measure movement towards stewardship goals in animals and humans, improved surveillance and data systems are essential. Better data will inform the public and allow for tracking of progress and evaluation of specific interventions. Building Block-4: Identifying and closing critical gaps in knowledge needed to address AMR Adequate surveillance underpins all of the actions necessary to fully address antimicrobial resistance. Currently, many countries lack the ability to not only accurately measure the scope and spread of resistance, but also to measure antibiotic use and assess the impact of different interventions and policies. Improved data collection systems at the national and local levels are needed in order to bolster current efforts and improve interventions in the future. These surveillance systems should monitor all aspects of the problem. Within human health, surveillance systems should ideally monitor rates of resistant infections both in hospitals, as well as the community, in order to accurately describe the burden of resistance. Also important, and more feasible in the short-term, are systems to collect data on antibiotic usage patterns in these different settings to better facilitate stewardship efforts. Policies that encourage increased uptake of surveillance systems to ensure a majority of facilities participate. 4 KK Trivedi and J Rosenberg. The State of Antimicrobial Stewardship Programs in California. Infect Control Hosp Epidemiol. 201; 34(4): 379-384. 5 Policy Statement on Antimicrobial Stewardship by the Society for Healthcare Epidemiology of America (SHEA), the Infectious Diseases Society of America (IDSA), and the Pediatric Infectious Diseases Society (PIDS). Infect Control Hosp Epidemiol. 2012; 33(4): 322-327.
An example of the potential for progress around human health surveillance in the U.S. is the CDC s launch of an Antibiotic Use and Resistance (AUR) module as part of the National Healthcare Safety Network (NHSN) surveillance system. The NHSN is already widely used by hospitals and other medical facilities throughout the U.S. to track healthcare-associated infections. The AUR module will allow these facilities to benchmark antibiotic use and resistance in their facilities, and will eventually enable the CDC to conduct national surveillance. However, the number of hospitals currently using the AUR module is low, and additional work must be done to increase uptake. In animal agriculture, there also is a need to measure how antibiotics are being used in the various species of food animals as well as a review of effective alternatives to antibiotic use (vaccines, increased hygiene, probiotics) that exist globally. In Denmark, authorities have enforced limits on antibiotic use in farming by collecting records of veterinary antibiotic use, inspecting farms where problematic overuse is suspected, and issuing warning citations (or yellow cards ) and fines for repeat offenses. Beyond the need for individual countries to improve data collection within their borders, assessment at an international level will require harmonization of surveillance systems. Current systems often vary by population, definitions and methodology. Increased regional and international coordination such as the European Antimicrobial Resistance Surveillance Network (EARS-Net) and the European Surveillance of Antimicrobial Consumption (ESAC-Net) would facilitate assessment of resistance and antibiotic use on a global scale. Building Block-5: Developing an innovative and sustainable approach to develop and distribute critical products and technologies needed to address AMR As noted above, the global pipeline of new antibiotics is inadequate to address emerging and future resistance. Drug makers developed at least 14 new classes of antibiotics between the 1930s and 1960s, 6 but only two new classes of systemic antibiotics since that time. 7 Furthermore, the antibiotics in the pipeline do not address all types of resistant bacteria in the clinic today, leaving gaps in treatment options for many patients with serious infections. Few major pharmaceutical companies remain involved in antibiotic development. Addressing the pipeline requires (1) improving the economic return on antibiotic research and development; (2) ensuring robust but efficient regulatory requirements and development pathways for high-need antibiotics; and (3) addressing scientific gaps that impede drug discovery. 6 JM Conly and BL Johnston. Where are all the new antibiotics? The new antibiotic paradox. Can J Infect Dis Med Microbiol. 2005; 16(3): 159-160. 7 ARM Coates, G Halls, and Y Hu. Novel classes of antibiotics or more of the same? Br J Pharmacol. 2011; 163(1): 184-194.
The economics of antibiotic development remain daunting. A number of efforts notably, one led by the UK government and ongoing European discussions are evaluating fundamental changes to the current business models for antibiotics developers. Notwithstanding technical challenges, these efforts hold promise. In the near term, efforts to streamline regulatory approval pathways and overcome scientific challenges may be more successful. Regulatory approval for drugs to treat highly resistant bacterial infections is especially challenging because only a small number of patients contract such infections and meet the requirements to participate in traditional clinical trials. As noted above, Pew is supporting the efforts of congressional champions to develop a new regulatory approval pathway in the U.S. for limited-population antibacterial drugs that would address the greatest unmet needs of patients. Pew is also exploring the role that greater collaboration between industry and academic efforts could have in overcoming scientific barriers. Next Steps ( What contribution would your organization be able to make in implementing the global action plan? ) Pew is actively involved in combating antibiotic resistance in the United States, and is well suited to aid in the implementation of a broader global action plan although our work will remain focused on U.S. interventions and policies. Specifically, Pew is able to: Continue awareness raising activities in the United States on the need to incentivize drug development and to optimize the use of antibiotic in human and animal health; Advocate for evidence-based policy solutions in the United States; Review and provide comments on draft action plans; and Organize convenings of relevant stakeholders to further national policies and international coordination.