Background Antibiotics are drugs that work by killing bacteria or slowing their growth. However, some bacteria have developed ways to resist the effects of antibiotics, for example, by preventing antibiotics from entering the cell or pumping them out after the antibiotic enters. Bacteria that are able to survive in the presence of antibiotics will multiply and pass on their new genetic material that confers resistance to future generations of bacteria and, in some cases, to other types of bacteria. Resistance can arise in bacteria in humans, animals, and the environment, including in health care settings, and can spread through contact with infected people or animals, contact with contaminated water, soil or surfaces, or consumption of contaminated food. The spread of antibiotic resistance threatens not only the ability to fight bacterial infections but also threatens to reverse some significant medical gains. For example, in addition to treating infections, antibiotics have allowed for numerous medical procedures, such as joint replacements, caesarian sections, organ transplants, chemotherapy, and dialysis—all of which would be significantly riskier without effective antibiotics. Antibiotic resistance also poses a significant economic burden resulting from the direct costs of treating those with resistant infections and the loss of economic productivity from those who get sick or die. In the 2013 Threats Report, CDC identified 17 bacterial pathogens that the agency considers to be “urgent,” “serious,” or “concerning” because they have developed enough resistance to antibiotics to be considered a threat to human health. (See fig. 1.) According to CDC, certain types of bacteria, called gram-negative bacteria, are particularly worrisome because they are becoming resistant to nearly all drugs that would be considered for treatment. The most serious gram-negative infections can be acquired in hospitals or other health care settings and can cause pneumonia, bloodstream infections, wound or surgical site infections, and meningitis. Nine of the 17 bacterial threats on CDC’s threat list are gram-negative. One of the bacteria CDC considers to be an urgent threat—Clostridioides difficile (C. difficile)—is classified as a threat not because it is resistant to antibiotics, but because it is caused by the same factors that drive antibiotic resistance, such as antibiotic use. CDC estimates that C. difficile alone accounted for 12,800 deaths in U.S. hospitals in 2017. CDC’s 2013 Threats Report also identified one type of fungus—Candida auris—that it considered to be a serious threat (see text box). Candida auris Is a Resistant Fungal Threat Candida auris (C. auris) is an emerging infectious fungus that, according to the Centers for Disease Control and Prevention (CDC), presents a global health threat in part because it is highly resistant to anti-fungal drugs and is challenging to address. C. auris was first identified in Japan in 2009. CDC reported 806 confirmed cases in the United States, as of August 31, 2019. According to CDC, C. auris is highly transmissible and some commonly used hospital surface disinfectants appear to be less effective against C. auris. A CDC official told us C. auris is a good example of an emerging threat that requires more research and associated efforts to properly address. Addressing C. auris is challenging for reasons including the rise of resistance and limitations in diagnostic tests. According to CDC, there are three classes of antifungals available to treat C. auris. However, CDC has identified strains that are resistant to all three classes. A CDC official noted that getting new antifungals to market is challenging because, among other things, the demand for antifungals, relative to antibiotics, is low. Additionally, according to FDA, although reliable tests for identifying C. auris exist, commonly used laboratory tests may misidentify this fungus, posing a barrier to correct diagnosis. In 2018, the Food and Drug Administration (FDA) cleared a test based on mass spectrometry to identify C. auris, but this test cannot characterize resistance. FDA officials told us there are three FDA-cleared tests available for testing for other Candida species’ resistance to fluconazole. However, none of these tests can provide rapid results, such as within an hour. Finally, interpretation of culture-based diagnostic tests, which examine how well bacteria grow in the presence of an antibiotic, is challenging due to the lack of established interpretive criteria for C. auris, by both the Clinical and Laboratory Standards Institute, which promotes the development and use of voluntary laboratory consensus standards and guidelines within the health care community, and by FDA. U.S. spending on antibiotics in health care from 2010 through 2015 was estimated in one study to be nearly $56 billion, ranging from $8.4 billion to $10.6 billion annually. While CDC states that antibiotic prescribing improved nationally with a 5 percent decrease from 2011 to 2016, the agency estimated in 2017 that at least 30 percent of antibiotics used across both outpatient and inpatient settings are still prescribed unnecessarily or incorrectly and, therefore, are considered inappropriate. According to CDC, approximately 85 to 95 percent of the nation’s antibiotic use, by volume, occurred in outpatient settings from 2010 through 2015; and roughly 270 million antibiotic prescriptions— equivalent to 836 per 1,000 persons in the United States—were written in these settings in 2016. (For more information on antibiotic use in the United States, see text box.) Antibiotic Use in the United States A 2017 Centers for Disease Control and Prevention (CDC) report estimates that about 30 percent of antibiotics used in U.S. hospitals are inappropriate (unnecessary or prescribed incorrectly), and as much as 50 percent of antibiotics prescribed in outpatient settings—such as physicians’ offices, emergency departments, urgent care centers, and retail clinics—may be inappropriate. For example, CDC reports that each year, an estimated 47 million unnecessary antibiotic prescriptions are written in physicians’ offices and emergency departments. Most of these unnecessary prescriptions are for respiratory conditions most commonly caused by viruses— including common colds, viral sore throats, and bronchitis—that do not respond to antibiotics, or for bacterial infections that do not always need antibiotics, like many sinus and ear infections. Furthermore, CDC reports that even when antibiotics are needed, prescribers often favor drugs that may be less effective and may carry more risk over more targeted, “first-line” drugs recommended by nationally recognized antibiotic prescribing guidelines. (First-line drugs are the drugs generally recommended for initial treatment for a given diagnosis, often combining the best efficacy with the best safety profile or the lowest cost.) According to CDC, antibiotics are among the most frequently prescribed medications in nursing homes, with up to 70 percent of residents receiving one or more courses of systemic (non-topical) antibiotics in a year; CDC also cites studies showing that 40 to 75 percent of antibiotics prescribed in nursing homes may be inappropriate. CDC further reports that harms from antibiotic overuse include the risk of serious diarrheal infections from C. difficile, increased adverse drug events and drug interactions, and increased risk of infection with antibiotic-resistant organisms. According to CDC officials, “unnecessary” antibiotic use means the antibiotic was prescribed when no antibiotic was needed, based on clinical practice guidelines. “Inappropriate” antibiotic use includes both unnecessary antibiotic use, as well as inappropriate antibiotic selection, dosing, or duration when antibiotics are indicated. CDC officials also told us they consider “misuse” and “inappropriate use” to be synonymous terms. The National Action Plan and Federal Agency Responsibilities Vaccines Can Also Help Prevent Antibiotic Resistance While we did not include vaccines in the scope of this report, vaccines play a role in helping combat antibiotic resistance because they are designed to prevent infections, including resistant infections. In addition, by preventing infections from occurring, they can reduce the need to use antibiotics, which in turn, can slow the development of antibiotic resistance. For example, according to the Centers for Disease Control and Prevention (CDC), since introduction of the pneumococcal conjugate vaccine among children in 2000, rates of antibiotic-resistant infections caused by certain Streptococcus pneumoniae strains decreased by 97 percent among children under 5 and by more than 60 percent among adults. However, few vaccines are available that target antibiotic-resistant bacteria on CDC’s threat list. In September 2014, the President signed Executive Order No. 13676 (Executive Order), which directed that several federal actions be initiated related to antibiotic resistance. For example, the Executive Order directed the creation of the National Action Plan, which the White House released in 2015, to provide a roadmap for federal agencies to respond to the threat of antibiotic resistance. The National Action Plan set five major goals over 5 years related to (1) slowing the emergence of resistant bacteria and preventing the spread of resistant infections; (2) strengthening national One-Health surveillance efforts to combat resistance; (3) advancing the development and use of rapid and innovative diagnostic tests for the identification and characterization of resistant bacteria; (4) accelerating basic and applied R&D for new antibiotics, other therapeutics, and vaccines; and (5) improving international collaboration and capacities related to the first four goals. In addition, the National Action Plan discusses the importance of preventing and controlling infections, such as through rapid detection, to combat antibiotic resistance domestically and globally (see text box). Within each of these five goals, the National Action Plan contains numerous objectives, sub-objectives, agency-specific milestones, and other performance targets called significant outcomes. For example, the National Action Plan set a significant outcome of reducing inappropriate antibiotic use by 50 percent in outpatient settings and by 20 percent in inpatient settings by 2020. According to the World Health Organization (WHO), effective infection prevention and control measures are a practical and scientific approach to reduce health care- associated infections in patients and health care workers, and help combat antibiotic resistance. Infection prevention and control measures serve as the cornerstone of actions needed to address epidemics, pandemics, and antibiotic resistance. Such measures include implementing hand hygiene practices, providing vaccinations, cleaning and disinfecting hospital rooms, isolating patients with infectious diseases, decontaminating and sterilizing medical equipment, and tracking data about emerging infectious diseases. WHO states that health care-associated infections are a global challenge from which no country or health care facility is immune. The Centers for Disease Control and Prevention (CDC) has taken actions to address and track health care-associated infections, including antibiotic-resistant infections. For example, in 2009, CDC issued guidance for infection control targeting Enterobacteriaceae that may be resistant to carbapenem, a class of antibiotics. In 2018, CDC published a study suggesting that a tracked decline in the proportion of resistant bacteria, including carbapenem-resistant Enterobacteriaceae, observed in some health care settings, could be attributable—at least in part—to actions such as those outlined in its 2009 guidance. In addition, CDC has reported that U.S. hospitals have made major progress since 2005 in declining rates of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia because of infection prevention measures. The interagency CARB Task Force, which was created by the Executive Order to issue and monitor the implementation of the National Action Plan, is co-chaired by the Secretaries of Defense, Agriculture, and HHS, and is additionally comprised of representatives from VA and several other agencies. Representatives from HHS agencies—including BARDA, CDC, CMS, FDA, and NIH—make up nearly two-thirds of the task force’s participants (see table 1). According to the HHS Assistant Secretary for Planning and Evaluation officials who coordinate it, the task force is developing a new National Action Plan that will span the years 2020 through 2025. To provide additional advice to the CARB Task Force and the Secretary of HHS, the Executive Order also created the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (PACCARB), which is composed of 15 non-governmental members. The Executive Order also charged the CARB Task Force with providing annual updates to the President regarding progress made in implementing the National Action Plan, plans to address any barriers preventing its full implementation, and recommendations for any new or modified actions, taking federal government resources into consideration. Since 2015, the CARB Task Force has produced four progress reports, which summarize agency actions toward meeting the goals and milestones laid out in the National Action Plan; these reports were provided to the President and are publicly available. CDC Has Expanded Surveillance of Antibiotic Resistance, but Faces Challenges Determining the Magnitude of the Problem CDC Has Expanded Surveillance of Priority Bacteria Since the National Action Plan was released in 2015, CDC has made progress in expanding surveillance for antibiotic resistance in the United States and abroad. However, the magnitude of the problem and its trends over time remain unknown, in part because of challenges in three areas: (1) tracking antibiotic resistance across all health care settings, (2) reporting complete and timely information on magnitude and trends of antibiotic resistance, and (3) tracking and assessing the global antibiotic resistance threat. To better assess the full extent of antibiotic resistance, CDC has expanded its surveillance of priority bacteria in the United States in order to better assess the full extent of antibiotic resistance since the 2015 National Action Plan was released. CDC tracks antibiotic resistance through several infectious disease surveillance systems in collaboration with state and local health officials, health care providers and facilities, and laboratories. Rather than establishing a single surveillance system for antibiotic resistance, CDC generally incorporates tracking of antibiotic resistance into broader surveillance systems, according to agency officials. The surveillance systems are spread across various divisions within CDC that specialize in specific types of infection or certain settings. (See table 2 for a description of each system and the resistant bacteria it tracks.) According to CDC and other officials and documents we reviewed, including the National Action Plan Year 3 Progress Report, CDC has taken the following actions, among others, to expand surveillance in order to better assess the scope of antibiotic resistance: Established the Antibiotic Resistance Laboratory Network in 2016 to improve testing capacity to better identify antibiotic resistance in the United States. The network consists of 55 state and local (including Puerto Rico), and seven regional, public health laboratories and the National Tuberculosis Molecular Surveillance Center. The network is improving and expanding laboratory capacity response at public health laboratories around the country, as well as at regional centers, according to representatives from two national professional organizations of state and local health officials and epidemiologists. Expanded antibiotic resistance-related efforts in its Emerging Infections Program (EIP), a network that seeks to monitor, prevent, and control emerging infectious diseases. For example, since 2015, more of the existing 10 EIP sites are conducting surveillance for invasive Staphylococcus aureus infections, carbapenem-resistant Enterobacteriaceae, and C. difficile, among others. Separately, the National Action Plan had included a goal for CDC to expand EIP by adding up to 10 sites within 3 years. However, CDC officials told us that in light of resource limitations, they chose to instead increase the number of pathogens reported at existing EIP sites. They told us they determined this was a better use of the limited funds, and that existing EIP sites are sufficient for current EIP efforts related to antibiotic resistance. Updated the domestic tuberculosis surveillance system by incorporating advanced drug susceptibility testing and reporting and by developing capacity for state surveillance systems to report their tuberculosis test data electronically to CDC laboratories. Supported state and local health departments to better track, investigate, and prevent resistant foodborne disease, among other things, through the National Antimicrobial Resistance Monitoring System for Enteric Bacteria (NARMS). For example, the system can now carry out whole genome sequencing for all the pathogens it tracks, which enhances its detection and response capabilities, such as by expanding CDC’s ability to detect new and emerging resistance, according to CDC officials. Launched the Enhanced Gonococcal Isolate Surveillance Program (eGISP), which augments the main Gonococcal Isolate Surveillance Program (GISP). Whereas GISP only collects samples from the urethras of men with symptoms of gonorrhea, in select sexually transmitted disease clinics, eGISP also collects samples from women and from other sites on the body, such as the throat. The specimens are sent to regional laboratories for resistance testing. CDC has also worked with international partners to expand surveillance of antibiotic resistance abroad. These efforts involved CDC collaborations with WHO, the European Center for Disease Prevention and Control, the government of the United Kingdom, other governments, and other multi- country efforts, such as the Surveillance and Epidemiology of Drug- Resistant Infections Consortium and the Transatlantic Taskforce on Antimicrobial Resistance (TATFAR). The collaborations aimed to develop technical guidance to help improve surveillance in other nations and to organize an international forum. CDC also launched its Antibiotic Resistance (AR) Solutions Initiative, which invests in national and international infrastructure to address resistant infections across health care settings and communities and from food. The Precise Magnitude and Trends of Antibiotic Resistance Are Unknown, in Part Because of Challenges CDC Faces in Three Areas CDC faces three general challenges in tracking and reporting trends in antibiotic resistance. First, it faces limitations in data reporting and resistance testing from hospitals, as well as challenges ensuring that its resistant gonorrhea surveillance system is representative of the U.S. population. Second, CDC faces challenges in reporting complete and timely information on the magnitude of and trends in antibiotic resistance. Finally, CDC faces challenges to detecting resistance threats abroad. Challenges in Tracking Resistance The first challenge CDC faces in tracking trends in resistance is addressing low hospital participation in a new option of CDC’s National Healthcare Safety Network (NHSN) system intended to address some limitations in NHSN. NHSN is, among other things, an online system for tracking health care-associated infections. It provides facilities, states, regions, and the nation with data needed to identify problem areas, measure the progress of prevention efforts, and ultimately eliminate health care-associated infections, according to CDC. Patients in settings such as hospitals and long-term care facilities (e.g., nursing homes) in many cases already have a weakened immune system or an underlying illness, making an antibiotic-resistant infection especially dangerous, according to the Centers for Disease Control and Prevention (CDC). A high proportion of the morbidity and mortality associated with antibiotic resistance is seen in health care-associated infections. Tracking resistance in health care settings is therefore critical to national surveillance efforts. CDC established three modules within NHSN that allow hospitals to report select antibiotic-resistant infections, among other things, which include reporting required by states or by CMS, according to agency officials. Two modules track patients who have an infection associated with a medical device or resulting from a surgical procedure. Hospitals only report on resistance in these modules for specific combinations of antibiotics and bacteria, such as carbapenem-resistant Enterobacteriaceae. The third module tracks certain hospital patients who test positive for certain multidrug-resistant infections, including methicillin- resistant Staphylococcus aureus (MRSA)—a type of bacteria found on people’s skin that is usually harmless but can cause serious infections, according to CDC. However, according to CDC, many antibiotic- resistant infections detected during hospital care do not fall into one of these three modules and therefore would not be captured in NHSN, limiting CDC’s ability to identify important new resistances or trends. In 2014, to help address this limitation, CDC officials told us they introduced a new option for hospitals to report data on antibiotic resistance—the Antimicrobial Resistance Option (AR Option). This option allows for reporting of data on antibiotic resistance for certain bacteria, regardless of whether the patient has a health care-associated infection. In contrast to the other three modules, reporting to the AR Option is voluntary. As a result, while about 86 percent of the 17,529 eligible U.S. health care facilities participate in at least one of the older three antibiotic-resistance reporting modules, only about 10 percent of the 6,836 eligible hospitals participate in the newer, voluntary AR Option, according to our analysis of NHSN hospital participation data as of January 2020. The hospital participation rate among U.S. states and territories ranged from no participation (in nine states and territories) to about 27 percent. Representatives from a national association of state public health officials we interviewed said that this low rate limits the value of the data, a view that echoed the findings of a 2018 report by the Joint Public Health Informatics Task Force. CDC officials acknowledged that participation in the AR Option is low and cited reasons for this, including hospital resource limitations, and—in many cases because participation is voluntary—because hospitals do not prioritize submitting data to the AR Option. According to CDC officials, it is particularly challenging for many smaller hospitals and Indian Health Service facilities with resource constraints to participate, as it requires significant information technology investment. The Joint Public Health Informatics Task Force report noted two other common challenges: low capacity for information technologies needed to support data submission to the AR Option, and a lack of motivated leadership, such as a facility “champion,” to oversee the development and maintenance of needed reporting infrastructure. For example, the maintenance of reporting infrastructure could address changes to electronic medical records that are not immediately compatible with the AR Option reporting format. CDC officials told us the agency is taking some steps to increase participation in the AR Option. For example, it is encouraging the over 1,500 hospitals (as of December 31, 2019) that are participating in a related reporting effort—known as the Antimicrobial Use Option (AU Option)—but not in the AR Option to participate in both. In addition, the agency is working with vendors of equipment and electronic health record software to make it easier for hospitals to participate in the AR Option. One of CDC’s goals for the AR Option is to use reported data to conduct regional and national assessments of resistance. To help meet this goal, officials said they would like participation by all eligible hospitals in the AR Option, but they have not determined the needed participation rates or appropriate distribution of participating hospitals. Our past work has shown that leading practices for federal strategic planning include articulating specific goals, establishing a method to assess progress toward these goals, and aligning the plans and goals with the agency’s mission. By taking steps to determine the participation rates and distribution of participation hospitals needed for CDC to meet its goal of conducting regional and national assessments of antibiotic resistance of public health importance, CDC would have more reasonable assurance that it can achieve its goal. The second challenge CDC faces is ensuring representativeness of its resistant gonorrhea surveillance system. CDC has classified resistant gonorrhea as one of the most urgent antibiotic-resistance threats in the nation, affecting over half a million patients annually. According to the agency, resistant gonorrhea warrants this designation because of the limited remaining treatment options, the high number of gonorrhea infections, potential adverse outcomes (such as increased transmission of HIV), and the prospect that gonorrhea may become incurable if new resistance arises and spreads. The Urgent Threat of Resistant Gonorrhea According to the Centers for Disease Control and Prevention (CDC), gonorrhea is the second most commonly reported notifiable disease in the United States, with over 500,000 infections reported in 2017. However, CDC estimates that the true number could be as many as 820,000 each year. In addition to being a very common infection, gonorrhea is developing resistance to treatment options. As recently as 2006, CDC had five recommended options, but it estimates that nearly half of U.S. infections are now resistant to available antibiotics, including combinations. Consequently, it now recommends only one regimen. In 2014, a case of dual-therapy failure was reported in the United Kingdom, and in February 2018, a similar case in the United Kingdom was reported that also failed to respond to the last-resort therapy, spectinomycin, resulting in treatment failure. As of June 2019, CDC reported that it had not received any reports of verified clinical treatment failures to any cephalosporin in the United States. It is not clear, however, that GISP data are representative of the general U.S. population because GISP draws on a limited sample of that population. Specifically, GISP collects culture specimens—-called isolates—and accompanying epidemiologic data from only the first 25 men with inflammation of the urethra consistent with gonorrhea visiting each participating sexually transmitted disease clinic each month. It does not collect culture specimens from women. In addition, the number of participating clinics each year has varied from 21 to 30 (see fig. 2 for the current sites). CDC estimates that the cases of gonorrhea identified through GISP surveillance represent only about 1 to 2 percent of all reported cases of gonorrhea in the United States each year. Further, the GISP sample design also over-represents cases in the western United States, where antibiotic-resistant gonorrhea has tended to initially emerge, according to CDC. According to CDC, this design allows for more rapid detection of emerging resistance by ensuring a sufficient sample size from the western United States because resistance tends to emerge from that area. CDC has two projects—Strengthening the United States Response to Resistant Gonorrhea (SURRG) and eGISP— intended to, among other things, enhance domestic gonorrhea surveillance and learn more about the representativeness of GISP through limited testing of women and of body sites other than urethras, respectively. However, CDC’s current methodology may limit its ability to establish a representative trend. According to CDC officials, GISP could improve its representativeness by adding clinics or covering more of the population at its current sites. However, efforts to expand GISP would be difficult due to limited local capacity (see text box). Barriers to Expanding the Gonococcal Isolate Surveillance Program (GISP) GISP currently tracks a limited sample of the U.S. population. According to Centers for Disease Control and Prevention (CDC) officials, a more thorough expansion of GISP would be more difficult because of limited local capacity to conduct culture-based testing for resistance in gonorrhea. Specifically, laboratories increasingly use newer gonorrhea testing technology that gives more rapid results but cannot currently be used to test for resistance. This trend has contributed to the reduced capability of many laboratories to perform the gonorrhea culture-based testing for antibiotic susceptibility testing, to the point that many clinics cannot collect specimens for testing, according to CDC officials. Furthermore, officials said that adding new clinics to GISP would require financial and other resources for, among other things, establishing culture testing for resistance and information technology needed to report data to the system. Most gonorrhea cases are diagnosed outside sexually transmitted disease clinics. However, expanding GISP to non-sexually transmitted disease clinic sites could be particularly costly and inefficient, officials said, because these sites tend to see many fewer gonorrhea cases per year compared to sexually transmitted disease clinics; therefore they may not be able to contribute significant data to GISP. Through the Strengthening the United States Response to Resistant Gonorrhea (SURRG) project, CDC is currently exploring options to work with states to enhance gonorrhea testing capacity. This program was established in 2016 but has not received the funding needed to expand capacity to the extent CDC had planned. In addition, physicians and other providers have limited time to devote to data collection and reporting needed to participate in GISP. CDC officials also told us the reimbursement rates for providers for these services are inadequate. CDC has taken some steps to assess the representativeness of the current GISP design, but it has not conducted a comprehensive study to assess the representativeness of the trends identified in GISP. A 2015 CDC evaluation concluded that the representativeness of GISP was “good” on a scale of fair, good, or great. However, the evaluation covered only part of fiscal year 2014 and consisted of a limited comparison of selected demographic characteristics captured in gonorrhea cases identified in GISP to those captured through the National Notifiable Diseases Surveillance System, according to CDC officials, and which has its own limitations. Further, the results of this evaluation have not resulted in any changes to the GISP design. CDC officials told us they hope to learn more about the representativeness of GISP urethral isolates from testing women, patients in non-sexually transmitted disease clinic sites in the SURRG project and eGISP, and testing at other body sites, and then comparing some of these results to those of GISP. However, these efforts overall were not specifically designed to fully assess the representativeness of GISP and may not provide a sufficient assessment for impacting changes to the GISP design. CDC’s guidelines of efficient and effective public health surveillance systems state that, in order to be representative, the data from a public health surveillance system should accurately reflect the characteristics of the health-related outcome—such as resistant gonorrhea—under surveillance. A more precise evaluation of the representativeness of the surveillance system can be done via carefully designed studies to obtain complete and accurate data for the health event in question—namely, the urgent threat of antibiotic-resistant gonorrhea. By evaluating the surveillance system for resistant gonorrhea to ensure that it includes measures of its representativeness, such as by comparing the trends in the sample population with those in the overall U.S. population, using specially designed studies if needed, CDC would have better assurance that the trends detected in GISP accurately reflect the characteristics of the health-related outcome the system is designed to monitor. In addition to the limited design of GISP, CDC faces the challenge of competing priorities under reduced funding that precluded it from completing its plans to expand the SURRG project. The SURRG expansion was designed to address a National Action Plan goal of controlling resistant gonorrhea, among other things, but also affects surveillance, as CDC officials told us SURRG was established to address some limitations in GISP surveillance. Specifically, one of the plan’s milestones assigned to CDC is to maintain advanced capacity for rapid response to antibiotic-resistant gonorrhea for at least 20 state health departments. Such capacity includes detection, diagnosis, and investigation of suspected resistant cases within their state or region and assistance for health care providers in appropriately treating infected patients. CDC officials told us that because they received about half of the appropriations they had requested, CDC had to make cuts in some of their projects, and SURRG was one of those that CDC chose to reduce. Eight SURRG sites, rather than the 20 recommended by the National Action Plan, collect and analyze data. However, in its progress reports covering the first 4 years of the National Action Plan’s implementation, the CARB Task Force did not identify plans to address barriers related to expanding the SURRG project. The CARB Task Force coordinators told us that the progress reports have not identified plans to address barriers largely because the task force focused on reporting the agencies’ accomplishments in implementing the National Action Plan. The coordinators also said that, in response to our inquiries during this review, the task force intends to identify agencies’ plans for addressing barriers in the progress report to be published in fall 2020. The Executive Order directs the CARB Task Force to provide annual updates to the President on federal government actions to combat antibiotic resistance, including progress made in implementing the National Action Plan, plans for addressing any barriers preventing its full implementation, and recommendations for any new or modified actions, taking federal government resources into consideration. Without reporting its plans to address such barriers, the CARB Task Force has not provided all the information required by the Executive Order and has not fully carried out its role to facilitate and monitor implementation of the National Action Plan, which may reduce the effectiveness of federal efforts to combat antibiotic resistance. The third challenge CDC faces tracking antibiotic resistance is addressing limitations to the use of test results in surveillance in health care settings. For example, some health care facilities are not using the most up-to-date testing methods for determining whether the bacteria causing an infection are resistant to certain antibiotics, according to CDC officials and a report from the Antibiotic Resistance Surveillance Task Force. In addition, laboratories may only report an interpretation of the test result to CDC (e.g., whether the bacteria is resistant or susceptible to an antibiotic) and not the quantitative results (e.g., measures of the growth of bacteria in the presence of the antibiotic). This presents a challenge for comparing data from different laboratories, since they may not be using consistent testing thresholds for determining antibiotic resistance. Another limitation is that some test equipment may be designed to give limited results for the purposes of guiding treatment recommendations and stewardship efforts, which may also limit the information available to CDC. For example, the test may inform the user that the infection is susceptible to one antibiotic but “suppress” information on susceptibility to other antibiotics, in order to guide the user toward treatment with the preferred first-line treatment. The Antibiotic Resistance Surveillance Task Force report noted that some suppression is done by the testing equipment itself and some by software systems that record, manage, and store data for clinical laboratories. CDC officials told us they are working with some diagnostic test manufacturers to explore these issues and develop solutions to address them. The Antibiotic Resistance Surveillance Task Force is also working to address the diagnostic test challenges related to antibiotic resistance surveillance. Challenges in Reporting Complete and Timely Information on Magnitude and Trends CDC also faces challenges in reporting timely and complete information on the magnitude of and trends in antibiotic resistance in the agency’s Threats Reports. One challenge is in providing information in these reports on the uncertainties in reported numbers of deaths from antibiotic- resistant infections. Another challenge is in issuing such reports in regular, timely intervals. As a result of these challenges, among others, the true magnitude of, and trends in, antibiotic resistance over time are unknown, including trends in various places and among people with various characteristics. Surveillance for antibiotic resistance is complex and costly, according to experts at our meeting, CDC officials, and literature we reviewed. Experts told us such surveillance encompasses diverse pathogens, diseases, and health care settings and requires a variety of data sources and collection efforts. Furthermore, experts from our meeting told us the fundamental data required—such as data on the number of illnesses and deaths attributable to resistance and data on related health care costs—are currently insufficient. One expert added that there is a lack of real-time monitoring data, such as data that are available within hours or days of being generated. The data gaps are especially large for infections acquired in the community, as opposed to in a health care setting, because there is very limited tracking of such infections and whether they are resistant. As a result, CDC officials said, it is challenging to provide ranges of uncertainty, a critical component of any effort to measure and report on magnitude and trends. Neither the 2013 Threats Report nor the 2019 Threats Report provided quantitative measures of uncertainty, such as confidence intervals, for CDC’s estimates of morbidity and mortality resulting from antibiotic- resistant infections. For example, the report stated that there are at least 23,000 deaths a year as a direct result of antibiotic-resistant infections, but it did not include an upper limit or a single point estimate for this number. Similarly, the 2019 Threats Report stated that there are at least 35,900 deaths a year, without an upper limit or a single point estimate. A recent re-estimate by a group of scientists has put the likely minimum number of deaths annually in the United States at approximately 153,000, or about four times the 2019 CDC minimum estimate. CDC officials told us that because of several limitations, its estimates were the best that could be derived from the data available. For example, for the 2013 Threats Report, CDC only had data from a national hospital survey intended to produce estimates of all health care-associated infections and indirect estimates of the proportion of infections that were resistant. These data did allow CDC to calculate confidence intervals for infections by specific pathogens, but this information was not disclosed in the Threats Reports. Because the data sources were not intended for this purpose, the 2013 intervals were wide, from approximately 26 percent to 380 percent of the point estimates for each pathogen. CDC officials told us they elected not to include these ranges of uncertainties to avoid confusion in the 2013 Threats Report, because the report was intended for a variety of audiences, including the general public. Officials told us they planned to provide confidence intervals in an appendix of the 2019 Threats Report, but they did not. CDC officials explained that they elected not to include confidence intervals in the 2019 Threats Report because several publications are pending that provide more granular data for many of the estimates included in the report. It is thus unclear whether CDC plans to include any measures of uncertainties in future Threats Reports. Federal standards for agency dissemination of information it produces stipulate that when information products are disseminated, error estimates are calculated and disseminated to support assessment of the appropriateness of the uses of the estimates or projections. Providing measures of uncertainties in antibiotic resistance estimates, such as standard errors or confidence intervals, as appropriate, in its Threats Reports would help CDC and others compare information within and across reporting efforts, without having to consult multiple documents over time. CDC and others could use this information to draw appropriate conclusions about the characteristics of antibiotic resistance in the United States, including limitations associated with reported findings and conclusions. Additionally, CDC does not have a plan for timely, regular issuance of their Threats Reports. It took CDC over 6 years to update the 2013 Threats report. CDC officials told us this length of time between reports was in part because, following issuance of the 2013 Threats Report, the agency was focused on implementing priority actions to improve antibiotic resistance surveillance data, including those efforts prescribed by the National Action Plan. In some cases, implementing these actions involved new data collection efforts that took time to establish, including that it can take up to 2 years to get new surveillance variables cleared by the Office of Management and Budget (OMB), CDC officials told us. In addition, CDC officials said it is time consuming to coordinate across the decentralized structure of antibiotic-resistance tracking at CDC to compile a consolidated report. However, lack of timely, regular updates may affect the information available to the public as well as policy-makers. For example, the 2013 Threats Report stated that there are at least 23,000 deaths a year as a direct result of antibiotic-resistant infections. The 2019 report stated the number of deaths each year to be at least 35,900 deaths a year. This report also revised the 2013 estimate from 23,000 to 44,000 deaths a year, suggesting a nearly two-fold revision to the initial 2013 estimate. CDC officials told us they would like to publish the report more frequently than every 6 years, and that it is reasonable they would develop such a plan for frequency of publication following the 2019 report. However, they said the agency does not currently have a plan for how often it will release future consolidated reports. CDC’s attributes of efficient and effective public health surveillance systems include timely data dissemination for planning, implementing, and evaluating public health policies and programs. By developing a plan for more frequent dissemination of consolidated reporting on priority pathogens at regular intervals, CDC would have more timely trend data and other information necessary for users of the data, including policymakers, to prioritize, plan, implement, and evaluate public health actions to address antibiotic resistance. Challenges in Tracking and Assessing the Global Threat In October 2015, the World Health Organization (WHO) launched the Global Antimicrobial Resistance Surveillance System (GLASS). The objectives of GLASS are to foster national surveillance systems and harmonized global standards and estimate the extent and burden of antimicrobial resistance globally by selected indicators, among other things. As of November 2019, 86 countries were enrolled in GLASS, a 25 percent increase over 2018. Participants were in various stages of economic development (13 lower-income countries, 23 lower-middle- income countries, 17 upper-middle-income countries, and 33 high-income countries) and in all WHO regions. Seventy-five countries provided descriptive information on their surveillance systems for tracking antimicrobial resistance, and 57 countries provided resistance data for 2018. antibiotic resistance from the national surveillance systems of some countries are incomplete because of a lack of capability and resources for implementing standardized protocols, according to WHO officials. Moreover, most information on antibiotic-resistant infections is limited to laboratory test data and does not include epidemiological data, such as data on the patient and location, which could provide additional insight about the circumstances around the resistant infection. Also, a lack of a sampling strategy for the detection of cases that are antibiotic-resistant may bias the representativeness of the data and interpretation of results. Specifically, when case identification is done only on the population of patients that seeks medical care and is tested, or when testing of the population varies such as across health care settings, the incidence and trends determined from this population may not represent the total population of concern. Aggregated data reporting. Some countries report aggregated, rather than isolate, or infection-level, data to the WHO’s Global Antimicrobial Resistance Surveillance System (GLASS), a practice that WHO officials stated creates a challenge for data analysis and results interpretation. According to officials, such aggregation limits statistical analysis that can be performed and limits analysis of factors such as the specific antibiotic-resistant bacteria, or the age or gender of the patient, among other things. Surveillance is a complex function. Many different health care and public health professionals are involved in the multistep process for generating data, according to a WHO report on GLASS. According to WHO officials, obtaining the staff commitment and training needed to ensure high-quality data can pose a challenge to public health agencies and health care organizations. As we noted above, CDC has worked with, and continues to work with, international partners to expand surveillance of antibiotic resistance abroad, including through U.S. participation in GLASS. For example, CDC has helped develop technical guidance for surveillance programs in other countries and has organized international forums for surveillance. CDC officials also told us portions of domestic surveillance systems data collection include collection of patient travel history. Federal Agencies Have Helped Advance Diagnostic Tests and Promoted Their Use, but These Efforts Have Limitations Federal agencies have helped advance the development of new FDA- authorized tests and the use of existing tests for diagnosing antibiotic- resistant infections, but these efforts have limitations. Specifically, HHS and DOD have funded studies and taken other steps to advance testing, but they have not defined leadership, roles, and responsibilities to address a key barrier to the use of tests: a lack of clinical outcome studies. FDA has taken additional steps to advance testing; however, it has not regularly monitored test updates. Agency Efforts toward the Development and Use of Diagnostic Tests HHS and DOD Have Funded the Development of New Tests HHS and DOD have awarded grants and contracts for the development of new FDA-authorized tests for diagnosing antibiotic-resistant infections. Some of these awards address specific needs in the current availability of FDA-authorized tests, while others support more general research and development efforts. In addition, these agencies have taken steps to help reduce the chances of duplicative funding. According to experts, tests for antibiotic resistance not only help clinicians decide what antibiotics to use, they also provide important information for surveillance, including the number of cases of resistant infections in a population and the mechanisms of resistance. to the 2013 Threats Report. Differentiate between viral and bacterial infections. Such a test would be useful primarily in preventing use of antibiotics for viral infections, which can contribute to the development of resistance in bacteria, among other things. HHS and DOD have awarded funding to address these needs. For example: CARB-X—a program supported by NIH and BARDA within HHS—has awarded funding to a company to develop a rapid test to both diagnose gonorrhea and test for antibiotic resistance. CARB-X is funding other companies to, among other things, develop rapid testing for identification of and resistance in bloodstream infections, including for some priority bacteria. In September 2016, NIH and BARDA announced the Antimicrobial Resistance Rapid, Point-of-Need Diagnostic Test Challenge. As of December 2019, there were five finalists, working on such projects as developing a rapid test to differentiate viral from bacterial infections and developing a test that can identify or detect antibiotic-resistant bacteria, including antibiotic-resistant gonorrhea. Within DOD, the Defense Advanced Research Projects Agency officials told us that the agency used fiscal year 2015 funding on contracts for the development of rapid molecular tests for resistant gonorrhea and to distinguish between viral and bacterial infections. Federal agencies have also funded more general research and development efforts related to resistance testing. For example: NIH officials told us their agency has supported extramural projects related to the development of tests for antibiotic resistance by issuing grants and entering into contracts since fiscal year 2015. Separately from the Antimicrobial Resistance Diagnostic Challenge, BARDA entered into contracts with three organizations to develop tests focusing on the advanced stages of test development, including clinical trials, according to BARDA officials. Within DOD, the Defense Threat Reduction Agency is funding three projects using Other Transaction Authority or direct funding to a DOD Service laboratory, for developing tests. Federal agencies have also taken steps to help reduce the chances of duplicative funding, including working with some international efforts to develop tests, according to agency officials. For example, NIH reviews current and pending support of key project personnel prior to issuing of any research award, to help ensure NIH support complements support from other agencies and organizations. Similarly, officials from HHS’s Office of Global Affairs worked during the creation and launch of the NIH- BARDA challenge and an analogous United Kingdom innovation foundation competition called the Longitude Prize to help ensure these programs were designed to support different aspects of needed diagnostics. HHS Has Funded Some Studies of Clinical Outcomes, but Has Not Clearly Identified Leadership, Roles, and Responsibilities HHS has funded some studies to assess the extent to which testing patients to identify whether they have antibiotic-resistant infections leads to improved clinical outcomes, such as more effective treatment for patients or more judicious use of antibiotics. However, HHS has not identified relevant leadership, roles, and responsibilities among the HHS agencies that could fund such studies. Clinical outcome studies are important for encouraging the use of diagnostic tests for antibiotic resistance, among other things, because such studies can demonstrate the benefits of those tests. According to PACCARB, there is very limited information on why clinicians sometimes forgo diagnostic testing, but one possible explanation is that there may be limited data demonstrating the value of such testing. In the absence of such data, a clinician may choose to treat the patient immediately rather than using a test for antibiotic resistance that has unknown value. Research into the clinical outcomes associated with such testing could therefore be used to help promote the use of those resistance tests that are found to be beneficial. As a result, patient care could be improved and clinicians could be guided towards appropriate antibiotics to prescribe. Two HHS agencies have awarded grants for studies on the clinical outcomes of resistance testing, according to agency officials. For example, NIH provided grant support for a study that found, among other things, that using a rapid blood test for a range of potential bacteria and antibiotic resistance led to more judicious use of antibiotics. Similarly, officials from the Agency for Healthcare Research and Quality (AHRQ) stated that the agency is funding investigator-initiated grant studies to assess the impact of tests on antibiotic stewardship. However, agency officials only mentioned these and a few other examples of studies they have funded on clinical outcomes. International Needs for Diagnostic Tests for Antibiotic Resistance To better understand international needs for antibiotic resistance tests, we interviewed officials from international organizations and the Office of Global Affairs within the Department of Health and Human Services (HHS). A Public Health England official told us that United Kingdom users are not confident that these tests will have a clinical impact or be cost effective. Similarly, an official from a trade organization of British medical test manufacturers told us that the value of tests for antibiotic resistance needs to be captured and disclosed, especially because people are more willing to pay for treatment than for tests. However, other factors could also be important in determining which tests will be useful internationally. World Health Organization officials told us that they are working to determine what characteristics health care providers worldwide identify as key to making tests useful, so industry can develop such tests. They noted that tests designed for use in the United States may not be suitable for use in other countries. They also noted that laboratories in developing countries may not have the capacity to culture bacteria, so many need to use culture- independent tests. Office of Global Affairs officials told us that a big challenge is developing accessible tests for use internationally. Their ideal test would be inexpensive, rapid, and capable of point- of-care use. They noted that cost and usability are the barriers to test use, not technology, and that use of existing tests remains limited, including within the United States. Agency officials and experts agree that more needs to be done to evaluate clinical outcomes associated with use of diagnostic tests for antibiotic resistance. For example, in 2017, PACCARB reported that “there is a lack of clinical and economic outcome studies showing that any diagnostic test could prevent the emergence of antibiotic-resistant bacteria and would be cost effective.” Officials we interviewed from AHRQ, BARDA, CDC, FDA, and NIH all agreed with that PACCARB statement. Additionally, experts told us that such studies are lacking but important for advancing the use of tests. For example, one health care organization official told us the decision to adopt a test is based at least in part on whether there will be a clinical benefit. An infectious disease expert noted that to provide incentives for test use there needs to be some evidence that tests affect and improve care, but that most tests do not come with any evaluation of how they perform in practice. International organizations expressed similar opinions. One reason for the relatively low number of studies is that those agencies that could conduct or fund diagnostic outcome studies have not clearly identified leadership, roles, and responsibilities for doing so. Although they agree that more such studies are needed, they have not identified which agency or agencies should take the lead, and what the roles of the other agencies should be. Instead, agencies have offered differing views on what each agency could do. For example, BARDA officials told us their agency has not funded such studies because it generally does not play a role in test adoption. BARDA officials, as well as officials from DOD and NIH, said that CDC should play a role in funding or conducting the studies. However, CDC officials told us that a lack of resources has prevented their agency from doing so, and that the responsibility should fall at least partly on BARDA. Our previous work shows that key practices for interagency collaboration include identifying a lead agency (or, if leadership is shared, clearly identifying roles and responsibilities among the lead agencies), as well as clarifying the roles and responsibilities of all participating agencies. By taking these actions, agencies—including AHRQ, BARDA, CDC, FDA, and NIH—could more effectively address the need for clinical outcome studies. Those studies, in turn, could help demonstrate the value of diagnostic tests for antibiotic resistance, potentially increasing their use, improving patient care, and enhancing stewardship efforts. CMS and FDA Have Taken Steps to Advance the Use of Tests, but Experts Have Identified Challenges with Payments CMS and FDA have taken some steps to advance the use of tests, including those to identify antibiotic-resistant bacteria. For example, FDA established a Payor Communication Task Force, which helps facilitate communication between test manufacturers and payors. Such communication is important because payors decide whether tests will be covered by insurance, among other things. According to an FDA web page, by communicating with payors, test manufacturers could, for example, learn what data payors need to approve a test for coverage and then use this information to design clinical trials to provide that information. This process could reduce the time between when a test is cleared or approved by FDA and when it is covered. A similar step FDA and CMS took to advance the use of tests was to extend the Parallel Review program indefinitely, a move they announced in 2016. This program established a mechanism for FDA and CMS to simultaneously review clinical data, with the aim of reducing the time between FDA’s approval and CMS’s decision on whether to pay for the test. Experts told us challenges remain with test payments that may result in lower test use. For example, a PACCARB report states that “currently, for many diagnostic tests is not aligned with the value of the test,” and noted that supplementing payments for tests could drive test development and use. BARDA officials also told us that a major factor affecting adoption of new tests is the cost of the test relative to reimbursement. Additionally, experts, including those at our meeting, told us that test payments remain insufficient to encourage broad test use. For example, two experts from our meeting said that there is not always a clear link between the medical value of a test and the payment level for that test. One of these experts added that their laboratory decided not to adopt a test because low payment levels relative to costs made doing so a money-losing proposition. Three other experts we interviewed agreed that disparities between cost and payment can discourage test adoption. Regarding federal payments for tests involving CMS and their payments through Medicaid and Medicare, there are limits to CMS’s ability to address any disparities. For example, CMS officials told us the payments for some tests are based on a weighted, median, private-payor rates pursuant to the Protecting Access to Medicare Act of 2014, so CMS cannot specify the methodology used to set those rates. Further, for inpatient tests, Medicare pays hospitals a single, bundled payment per patient stay, which is based on multiple factors, including the patient’s diagnosis and treatment strategy, rather than on a specific service. As such, a separate payment for individual tests is not made under Medicare. FDA Efforts to Advance the Development of New Tests FDA Has Taken Steps to Speed the Development of Tests for Newly Approved Antibiotics FDA has taken steps toward the development of FDA-authorized tests for resistance for newly approved antibiotics—a process that currently can take months to years, according to experts and agency officials. The delay stems in part from the need for a critical testing threshold known as a breakpoint—the threshold that is used to help a clinician decide whether or not a pathogen is resistant to the antibiotic (see text box). The breakpoint of a new antibiotic is generally finalized only when FDA has approved the antibiotic. This means that breakpoints may often not be available for test manufacturers until after a new antibiotic is FDA- approved. As a result, test manufacturers generally may not be able to complete developing FDA-authorized culture-based tests for resistance to a specific antibiotic until after the antibiotic is commercially available. The result is that the development of such culture-based tests may be generally delayed even after the new antibiotic is approved by FDA. This delay could affect the ability of clinicians to treat patients. For example, according to an expert, such a delay could lead to underuse of a newly available antibiotic, among other things, because a clinician may not be willing to prescribe the antibiotic without test results to guide treatment. How Breakpoints Are Used to Interpret Tests According to officials from the Food and Drug Administration (FDA), breakpoints, also referred to as “susceptibility test interpretive criteria,” are used to define susceptibility and resistance to antibiotics to help guide patient care. Culture-based tests rely on breakpoints to provide a determination of resistance to clinicians. In the United States, breakpoints (based on clinical or microbiological data) are established by standards- development organizations such as the Clinical and Laboratory Standards Institute (CLSI) and FDA. One example of how breakpoints are used involves the Kirby-Bauer disk diffusion test. This test is conducted by spreading bacteria on a laboratory agar plate containing bacterial nutrients, and then placing paper disks containing a known amount of antibiotics on the “lawn” of bacteria. Plates are observed after overnight incubation to determine the extent of bacterial growth. Closer to the disk, there is a higher concentration of antibiotic, and the concentration declines with distance. Around most disks, there is a “zone of inhibition,” where the concentration of antibiotic is too high for bacteria to grow. After allowing the bacteria to grow for a defined period of time, the diameter of the zone of inhibition is measured in millimeters. Procedure for Assessing Antibiotic Resistance Using Breakpoints If the diameter is larger than or equal to the breakpoint, then the strain of bacteria is considered susceptible to the antibiotic, suggesting that the antibiotic can be used to treat infections caused by that strain. If the diameter is smaller than the breakpoint, then the strain is considered resistant, suggesting that the antibiotic should not be used. According to FDA, in most cases, there is a range of “intermediate” or “susceptible dose-dependent” diameters for which treatment might be effective. Other types of culture-based diagnostic tests for resistance have analogous breakpoints for interpreting the test. For example, the minimum inhibitory concentration—the lowest concentration of an antibiotic that prevents growth of bacteria—can be compared to a breakpoint to establish whether the bacteria are considered resistant. In addition to antibiotic developers waiting until FDA approves an antibiotic before a breakpoint is finalized, there are technical hurdles in developing a test for some new antibiotics, according to FDA officials. For example, it may be challenging for certain automated test manufacturers to address unique growth properties of certain bacteria in the presence of specific antibiotics or combinations of antibiotics. According to a test manufacturer, these hurdles include the need for additional studies, and such studies may not be straightforward because of the need to determine what clinical data FDA requires. In addition, in the case of automated tests, a representative from a test manufacturer association told us the software used to run and interpret a new test needs to be revised, which can be time consuming. The delay between approval of an antibiotic and the availability of a test for resistance could result in suboptimal treatment and increase burdens on the health care system. For example, one expert stated that during this delay, laboratories need to create or modify tests and then validate those tests instead of using a FDA-authorized test, which increases the time required and places demands on facility personnel and budgets. This expert added that to conduct validation studies, the laboratories need a variety of samples for testing, called “isolates,” which may not be available. A second expert said that the delay leads to both overuse and underuse of the new antibiotic: in the absence of a test, some clinicians will prescribe the antibiotic when it may be inappropriate, leading to overuse; some other clinicians refrain from prescribing the antibiotic, even if appropriate, leading to underuse. To help address this delay, FDA has created a process known as coordinated development, whereby test manufacturers can submit a coordinated development plan to FDA describing the test manufacturer’s intent to coordinate with the antibiotic manufacturer. The plan is submitted prior to, or shortly after, submission of an application to market a new drug. Under the coordinated development program, FDA shares breakpoint information from the antibiotic manufacturer with a prospective test manufacturer. It then reviews the test application at the same time as the antibiotic application and takes other steps to facilitate more timely clearance of the test. FDA officials told us this process has significantly reduced the delay between approval of the antibiotic and clearance of the test. Another FDA step to help test manufacturers speed development of tests is the establishment, in collaboration with CDC, of a centralized repository of bacterial strains with well-characterized antibiotic resistance profiles. These strains are available to test manufacturers and others to help them design, validate, and evaluate tests by checking that they give the correct results for bacteria whose profile of antibiotic resistance is known. Finally, FDA officials also said that they offer pre-submission advice, whereby a test manufacturer can ask for initial guidance on the design of clinical studies for their tests. FDA Has Taken Steps to Improve Breakpoint Recognition In the United States, breakpoints are established and updated by organizations such as the Clinical and Laboratory Standards Institute (CLSI). After CLSI establishes a breakpoint, FDA may review and recognize the breakpoint, according to FDA officials. Test manufacturers rely on breakpoints recognized by FDA to support marketing authorization of their tests. An expert who works for CLSI identified more than 50 breakpoints that have not been recognized by FDA, and for which CLSI considers FDA recognition important in order to help make FDA-authorized tests available. Experts, including one from our meeting, cited the following examples of breakpoints needing recognition: CDC recommends a dual therapy of antibiotics—azithromycin and ceftriaxone—to be taken together to treat gonorrhea. However, FDA does not recognize any azithromycin breakpoints for N. gonorrhoeae, which an expert from our meeting told us could be a barrier to developing FDA-authorized culture-based tests for N. gonorrhoeae resistance to the recommended dual therapy. Colistin is an antibiotic used in hospitals because of its efficacy against carbapenem-resistant bacteria, according to one manufacturer of a test for colistin resistance. This manufacturer markets its test in many countries but not in the United States, because FDA does not recognize colistin breakpoints. FDA has taken some steps to address unrecognized breakpoints, which are a potential barrier to developing some tests for antibiotic resistance. For example, FDA officials told us that the agency conducts regular internal reviews of breakpoints. According to FDA officials, the agency reviewed the 2019 CLSI breakpoint standards and updated FDA’s website with changes to recognized breakpoints as of June 2019. FDA has been posting such updates since December 13, 2017. FDA also accepts public comments requesting the recognition of new breakpoints, according to agency officials. However, we found there was some confusion between CLSI officials and experts and the FDA involving the number of comments FDA could review each year, which FDA later clarified on its website. One expert at our meeting later told us that CLSI adjusts its process for submitting comments based in part on their understanding of FDA’s communication. This expert added that FDA making a public commitment to a specific number of comments they would review would help CLSI improve its planning. FDA officials told us there is no legal requirement for FDA to communicate the number of comments the agency can review, but that in previously published notices of opportunities for public comments, there was nothing that indicated there would be limits. However, after we informed FDA officials of concerns by experts regarding the number of comments FDA could review, FDA updated their webpage to clarify that they will review all submitted comments. FDA Has Taken Limited Steps to Monitor Use of Updated Breakpoints FDA has taken limited steps to monitor whether FDA-authorized tests are using new breakpoints after these breakpoints are updated and accepted by FDA. Because bacteria can develop increasing resistance to antibiotics, it is sometimes important to change the breakpoints used for determining whether or not bacteria are resistant to a given antibiotic. Using tests with out-of-date breakpoints could result in misidentifying a resistant infection as non-resistant, which can lead to treating a patient with an ineffective antibiotic and the further spread of the infection. FDA officials told us the agency has taken limited steps to monitor the status of breakpoint updates, and that out-of-date breakpoints being used in tests should be a rare occurrence. In contrast, a CDC official told us that keeping tests updated is a significant concern. This official cited the example of carbapenem- resistant Enterobacteriaceae infection, which triggers specific procedures to limit the spread of these bacteria. If the test breakpoint is out of date, the infection may not be detected in a timely manner, and the pathogen could spread broadly as a result. A recent study looking at hypothetical scenarios in one U.S. county estimated that a 32-month delay in updating tests to match CLSI breakpoints for carbapenem-resistant Enterobacteriaceae would have resulted in an average of almost 2,000 additional carriers of these bacteria county-wide. Additionally, an expert told us that use of out-of-date breakpoints could lead to improper patient care, improper surveillance reporting, and slower detection of emerging resistance. However, the true impact of this issue is challenging to discern (see text box). The Extent of Any Negative Effects of Out-of-Date Breakpoints on Public Health Is Unclear Experts and agency officials voiced a range of opinions on the public health effects of tests with out-of-date breakpoints. For example, one Centers for Disease Control and Prevention (CDC) official told us that despite the lack of breakpoint updates, cases of a type of carbapenem-resistant Enterobacteriaceae were likely ultimately caught by hospitals because a second test was used by all but a small number of hospitals. One expert stated that how quickly test breakpoints are updated is less important when deciding what test to adopt than other factors, such as ease of use. However, another expert noted that laboratories addressing emerging threats may feel the need to use non-Food and Drug Administration (FDA) cleared tests, because they are aware that FDA-cleared tests may not be updated as quickly as needed. Test updates may be an issue for smaller laboratories, which do not have dedicated personnel keeping track of breakpoint revisions, Department of Veterans Affairs officials told us. FDA officials told us that because manufacturers are strongly motivated to keep their tests current, only a few tests have out-of-date breakpoints. However, the only confirmation FDA officials offered for this statement was to mention an unofficial internal survey of FDA’s database of existing tests, conducted in March 2019, which concluded that all FDA-authorized tests had implemented breakpoint updates made since December 13, 2017. They said this survey is not conducted regularly. They also stated that it is possible that some tests have not been updated to reflect breakpoint updates made prior to December 13, 2017, but that FDA is unaware of any such tests that also pose a public health threat. To assess the extent to which there are FDA-authorized tests using out- of-date breakpoints, we spoke with experts and stakeholders and reviewed studies they identified. We identified several FDA-authorized tests with breakpoints that were changed nearly a decade ago. Some of these tests could be used for diagnosing infection with carbapenem- resistant Enterobacteriaceae, which CDC identified as an urgent threat. One manufacturer told us that one of their tests has not been updated with new breakpoints nearly 10 years after a breakpoint revision. FDA officials acknowledged it is possible some FDA-authorized tests might continue to rely on outdated breakpoints. Further, in 2019, a scientific article listed four different test manufacturers offering tests that have not been fully updated to reflect revised breakpoints, including some affecting antibiotics for some types of carbapenem-resistant Enterobacteriaceae. Finally, CDC officials told us they asked hospital laboratories in a survey for 2017 and 2018 if they had updated their tests to reflect revisions in breakpoints for carbapenem-resistant Enterobacteriaceae that were implemented in 2010. According to CDC, nearly 1,000 of over 5,000 responding hospital laboratories had not implemented the revised breakpoints, and, of these, over 85 percent were using FDA-authorized tests. One CDC official stated that there is significant concern for patient safety associated with out-of-date breakpoints, and another said that there are few justifications for failing to update the tests after 8 years. FDA officials told us they have not received reports of suspected device-associated deaths, serious injuries, or malfunctions that are specific to out-of-date carbapenem-resistant Enterobacteriaceae breakpoints in FDA-authorized tests using such breakpoints. The officials added that it is possible to detect carbapenem-resistant Enterobacteriaceae under certain situations, even if the test had an out-of-date breakpoint for a given antibiotic against these bacteria. However, FDA does not know the actual negative effect, if any, of out-of- date breakpoints because it does not know how many FDA-authorized tests rely on such breakpoints. Since December 2017, FDA has conducted one unofficial survey of tests to assess breakpoint updates that was limited in scope and is not a regular event. Other than that, FDA is relying on market incentives to drive manufacturers to make sure their devices are updated. According to FDA and others, the extent of the problem is not clear. However, PACCARB identified updating test breakpoints as an important issue in a 2017 report. Additionally, one of the sub-objectives in the National Action Plan notes that rapid updating of breakpoints is essential to provide accurate information to guide appropriate drug treatment. Finally, the Standards for Internal Control in the Federal Government directs management to establish and operate monitoring activities to monitor its internal control systems and evaluate the results. In this case, monitoring and evaluation of the status of breakpoint updates in FDA-authorized tests could help FDA identify and address the National Action Plan sub-objective, as well as a strategic priority in the mission statement of its Center for Devices and Radiological Health: “FDA assures that patients and providers have timely and continued access to safe, effective and high-quality medical devices.” FDA officials said they do not believe the issue is a significant problem, but the agency has also not regularly evaluated any effects of using tests for antibiotic resistance with out-of-date breakpoints. FDA officials stated that there may be resource constraints to their ability to conduct regular monitoring and evaluation. By regularly monitoring and evaluating FDA-authorized tests, FDA would be better positioned to determine the extent of tests relying on out-of-date breakpoints and may be better positioned to provide assurance that patients and providers have timely access to safe and effective tests. Furthermore, by regular monitoring, FDA would be able to determine whether test manufacturers are updating breakpoints as needed, and help ensure that patient care and infection control efforts are effective. Federal Efforts Have Not Fully Addressed Challenges to Developing New Treatments for Antibiotic-Resistant Infections Experts, federal officials, and antibiotic developers have identified economic and other challenges to developing new antibiotics. Federal agencies, including HHS and DOD, have engaged in efforts to address some of the challenges; however, experts said these efforts are not sufficient and that additional federal incentives are needed to encourage the development of new antibiotics. Economic and Other Challenges to Developing New Treatments Exist Experts are concerned about a void in the discovery of new antibiotic classes and the current pipeline of antibiotics in development. According to The Pew Charitable Trusts, a nonprofit public policy organization that tracks the pipeline of antibiotics, no new classes of antibiotics approved for human use have been discovered since 1984. In addition, experts are concerned that the number of antibiotics in clinical development is insufficient to meet the threat of antibiotic resistance. For example, according to The Pew Charitable Trusts, only 42 antibiotics were in clinical development globally—meaning clinical trials were being conducted to test their safety and efficacy in humans—as of June 2019, and only 24 of them targeted bacteria on CDC’s or WHO’s priority lists. According to a recently published analysis, the authors found that the pipeline of antibiotics that target gram-negative bacteria is dominated by derivatives of existing classes of antibiotics and “does not sufficiently address the problem of extensively drug-resistant gram-negative bacteria”. For example, one study estimated the average cost per new molecular compound that received FDA approval between 2005 and 2013 to be $1.4 billion. See J. A. DiMasi, H. G. Grabowski, and R. W. Hansen, “Innovation in the Pharmaceutical Industry: New Estimates of R&D Costs,” Journal of Health Economics, vol. 47 (2016): pp. 20-33. Other studies suggest lower development costs. For example, another study estimated a median cost to develop cancer drugs of $0.6 billion. See V. Prasad and S. Mailankody, “Research and Development Spending to Bring Single Cancer Drug to Market and Revenues After Approval,” JAMA Internal Medicine, vol. 177, no. 11 (2017): pp. 1,569-1,575. for antibiotic-resistant infections have a narrow set of patients for whom the treatment would be appropriate. As a result of the perceived poor return on investment, many large pharmaceutical companies have discontinued their antibiotic development in recent years. In 2018, according to The Pew Charitable Trusts and other published sources, four large pharmaceutical companies worldwide had antibiotics in clinical development globally compared to 1990, when 18 were involved in antibiotic R&D. Two antibiotic companies declared bankruptcy in 2019; in the case of one, the company filed for bankruptcy only 10 months after its antibiotic, which targets resistant bacteria, received FDA approval. The majority of antibiotics in the development pipeline are being developed by smaller companies that do not have other drugs on the market to help cover their R&D costs. However, representatives from three small antibiotic developers we spoke with noted that their field is struggling because it is difficult to raise funds from private investors due to the low return on investment potential. with bacterial infections into certain clinical trials prior to initiating treatment can be difficult due to a lack of available rapid diagnostic tests to identify the type of infection and the urgent need to begin treatment immediately for acute infections. According to FDA officials, this is problematic for clinical trials because any prior treatment could obscure the true efficacy of the drug under investigation. Recognizing this often unavoidable issue, FDA has issued guidance giving antibiotic developers additional, but limited, flexibility with their clinical trial protocols in certain cases. Superiority trials, which aim to show that the drug being investigated is more effective than an existing drug. Non-inferiority trials, which aim to demonstrate that the difference between the effectiveness of the drug being investigated and an existing drug is small enough to show that the drug being studied is also effective. Typically, there are three phases of clinical trials, with the sizes of the trials increasing with each phase. FDA generally prefers that when conducting clinical trials, developers demonstrate the effectiveness of a new drug by showing its impact on a clinical endpoint— a direct measure of how a patient feels, functions, or survives. FDA also accepts surrogate endpoints, which are laboratory measures or physical signs used as a substitute for a clinical endpoint that reasonably predict a clinical benefit. developers told us that, for most antibiotics, it is difficult to conduct superiority clinical trials and more feasible to conduct non-inferiority trials, because the latter allows for smaller enrollment. (See side bar for an explanation of clinical trial types.) They told us that the inability to demonstrate their drug’s superiority limits their ability to market the drug, because it can be difficult to convince purchasers (e.g., hospitals) to choose the newly approved antibiotic over existing antibiotics, especially when the new antibiotic is significantly more expensive. Gaining approval for multiple indications. FDA generally approves drugs for a specific indication; therefore, antibiotic developers told us they tend to design their clinical trials around common infection types, largely because of the relative ease of enrolling patients. However, some antibiotics can treat infections in multiple parts of the body, which may not have been studied in a clinical trial. While providers are able to prescribe drugs for “off-label” use—that is, for a condition or patient population for which the drug has not been approved—they may lack information on the safety and efficacy of the drug for such use. In addition, such off-label use may not be reimbursed by the patient’s insurance. According to The Pew Charitable Trusts, there were 29 nontraditional antibacterial products in clinical development for the U.S. market in June 2019. Among the 29 products in the pipeline, nine were antibodies, seven were vaccines, seven were live biotherapeutic products, and six were other types of products. No bacteriophages were in clinical development. More than half of these products are for the treatment of Clostridioides difficile or Staphylococcus aureus infections. Experts, antibiotic developers, and federal officials also said it is scientifically challenging to develop new antibiotics that can overcome existing mechanisms of resistance. One expert at our meeting explained that it is necessary to develop an antibiotic that works differently than existing antibiotics so that bacteria are not resistant to it. In particular, experts and federal officials have noted that it is challenging to develop antibiotics that can kill certain types of bacteria, called gram-negative bacteria, largely due to their double membrane that makes it difficult for antibiotics to enter the bacterial cell, and to pumps that can remove the drug once it enters. Three antibiotic developers we spoke to explained that as bacteria continue to evolve new ways to resist antibiotics, it is difficult for scientists to keep pace by developing new treatments that can overcome those mechanisms. In addition, experts noted that scientists have already discovered most of the antibiotics from known sources, such as soil. As a result, scientists are now exploring new sources of chemicals with antibiotic properties, such as insects. As the rate of antibiotic discovery has slowed, scientists have also begun to explore alternatives to traditional antibiotics—which we call “nontraditional products” in this report. Many types of nontraditional products are currently being researched and developed to treat antibiotic- resistant infections, including, among others, live biotherapeutic products, antibodies, and bacteriophages. For example, one type of nontraditional product in use for the treatment of recurrent C. difficile- associated disease—which causes diarrhea, abdominal cramps, and an estimated 15,000 deaths in the United States each year, according to CDC—is fecal microbiota for transplantation, more commonly known as fecal transplants. (See text box.) However, scientists and companies researching and developing certain types of nontraditional products face development challenges. For example, according to a paper written by BARDA officials and others, certain types of nontraditional products target only one or a few types of bacteria, which makes enrollment of patients in clinical trials difficult and potentially cost-prohibitive. The authors also stated that additional research is needed to evaluate side effects and measure the efficacy of some types of nontraditional products. According to another published paper, more than half of the nontraditional products in development are intended to be used concurrently with a traditional antibiotic, and it can be difficult to demonstrate the additional clinical benefit of adjunctive therapies in clinical trials. The authors also noted that additional clinical trial endpoints still need to be developed and validated for such nontraditional products. Fecal Transplants The goal of a fecal transplant—which involves collecting stool from healthy donors and transferring it to patients via enema, oral capsule, or another modality—is to restore a healthy gut microbiome for recipients. According to the National Institutes of Health (NIH), multiple research studies have indicated that these transplants are effective, but their long-term safety has not been established. Questions remain about the Food and Drug Administration’s (FDA) policy regarding stool banks that collect, prepare, and distribute fecal transplant products. FDA issued guidance in 2013 indicating its intention to exercise enforcement discretion regarding Investigational New Drug requirements for the use of fecal transplants to treat Clostridioides difficile infections, provided that the treating physician obtained adequate consent from the patient or his or her legally authorized representative. In other words, FDA’s guidance indicated it would not require fecal transplant products to satisfy the Investigational New Drug requirements— which refer to the requirements for FDA’s approval before beginning clinical trials to test a product on humans. [FDA, Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation To Treat Clostridium difficile Infection Not Responsive to Standard Therapies; Guidance for Industry; Availability, 78 Fed. Reg. 42965 (Jul. 18, 2013).] However, FDA later issued draft guidance in 2016 stating that FDA did not intend to extend enforcement discretion with respect to the Investigational New Drug requirements applicable to stool banks distributing fecal products. [FDA, Enforcement Policy Regarding Investigational New Drug Requirements for Use of Fecal Microbiota for Transplantation To Treat Clostridium difficile Infection Not Responsive to Standard Therapies; Draft Guidance for Industry; Availability, 81 Fed. Reg. 10632 (Mar. 1, 2016).] FDA has not finalized the 2016 draft guidance, which leaves the final guidance from 2013 as the current policy. According to FDA, the agency received many comments from patients and industry groups in response to the 2016 draft guidance expressing concern about the effect that the requirement for clinical trials would have on access to these products. In March 2019, FDA officials told us they were still reviewing comments to the 2016 draft guidance and were unable to say whether or not it would be finalized. In November 2019, FDA held a public hearing to obtain further input on the use of fecal transplants to treat C. difficile infection not responsive to standard therapies and to better understand the effect of FDA’s enforcement policy on product development. Federal Agencies Have Made Some Progress toward Addressing Treatment Development Challenges Multiple federal agencies have supported the development of new antibiotic treatments, including providing funding for antibiotic R&D, issuing guidance related to antibiotic clinical trials, and implementing Medicare payment mechanisms. Agencies have made available both “push” incentives, which directly support antibiotic R&D, and “pull” incentives, which offer financial benefit, either directly or indirectly, to developers of successful antibiotics after they reach the market. Federal funding for antibiotic R&D. Several federal agencies award grants or contracts, create public-private partnerships, or use other approaches to provide researchers the funding for R&D of new treatments for antibiotic-resistant infections (see table 3). This type of pre- market R&D support is considered a “push incentive.” See appendix III for additional examples of efforts to support antibiotic R&D by NIH and DOD. Among the products in the CARB-X portfolio, 12 would represent a new antibiotic class (if approved) and 14 target a novel molecular bacterial target. Awardees were based in six countries. Issued guidance to support clinical trials. FDA has implemented programs and issued guidance that help address some regulatory challenges and encourage antibiotic development. In 2012, through the Generating Antibiotic Incentives Now provisions of the Food and Drug Administration Safety and Innovation Act, Congress created the Qualified Infectious Disease Product (QIDP) designation. Drugs that FDA designates as QIDPs, which include antibiotics and antifungals, may qualify for 5 years of additional exclusivity and fast-track or priority review designation during the FDA review process. The additional exclusivity conferred to QIDP designees is a type of “pull incentive,” because it offers the potential for enhanced financial gain after a drug receives FDA approval and reaches the market. According to FDA officials, as of September 2019, FDA had granted 192 QIDP designations, 24 of which it has approved for marketing. Also in response to the Generating Antibiotic Incentives Now Act, FDA released final guidance in August 2017 to streamline clinical development of antibiotics for patients with an unmet medical need—that is, those with a serious bacterial disease that has few or no treatment options. FDA explains in this guidance that it may consider drugs for these patients that have higher risks than would be acceptable for a broad patient population and provides information on types of antibiotics that could be eligible for approval based on smaller, shorter, or fewer—as few as only one— clinical trials. The 21st Century Cures Act required FDA to establish a Limited Population Pathway for Antibacterial and Antifungal Drugs (LPAD). In June 2018, FDA issued draft LPAD guidance, as required by the Act. Under LPAD, eligible products—which are drugs and biologics intended to treat a serious or life-threatening infection in a limited population of patients with unmet needs—may follow a streamlined development program, similar to the approaches described in its earlier unmet medical need guidance. A biotechnology association noted in its public comments to the draft LPAD guidance the need for FDA to issue additional guidance to clarify its expectations for acceptable types of efficacy data when clinical trials are small and to clarify its interpretation of a “limited population of patients” for the purpose of the LPAD pathway. An expert who attended our meeting later told us there is a great need to address how to develop narrow-spectrum antibiotics—those designed to treat a single or small number of bacterial pathogens—using LPAD. FDA held a public meeting in July 2019 to solicit stakeholder comments on the draft LPAD pathway guidance, and FDA officials told us they expect to finalize the guidance by February 2020. However, as of March 17, 2020, FDA had not yet issued final guidance. In addition to issuing guidance, and to help inform future guidance, FDA engages with industry stakeholders to discuss and identify possible solutions to challenges related to the clinical development of antibiotics and nontraditional products. For example, FDA has held multiple public workshops, including one in November 2019 with experts from NIH’s National Institute of Allergy and Infectious Diseases, the Infectious Disease Society of America, and The Pew Charitable Trusts to better understand the current state of antibiotic clinical trials in the United States, and how to enhance enrollment and research in these trials. FDA officials told us they believe it is too early to issue guidance that would be broadly applicable and useful to nontraditional product developers. They explained that for certain types of nontraditional products, the approaches and specifics of product development are varied and evolving quickly. Instead, FDA’s Center for Biologics Evaluation and Research has a program in place that allows developers to meet with FDA prior to beginning clinical trials to obtain advice on a wide range of development-related topics. Implemented Medicare payment mechanisms. CMS uses Medicare payment mechanisms to help increase reimbursement to hospitals for certain antibiotics. For qualifying antibiotics, these payments are a form of indirect pull incentive because they have the potential to increase the demand for the new antibiotics after they reach the market, which could in turn improve their financial performance. Beginning in fiscal year 2020, CMS updated how it will pay hospitals for treating Medicare patients who have an antibiotic-resistant infection. Specifically, CMS changed the eligibility criteria and payment amount for antibiotics that qualify for “new technology add-on payments” and how it pays hospitals for treating Medicare patients with antibiotic-resistant infections. These payment changes are: Revised eligibility criteria for and amount of add-on payments. New technology add-on payments provide hospitals with additional compensation for a period of 2 or 3 years when they use qualifying new technologies or drugs that offer substantially improved clinical treatment, and when regular Medicare payments for the hospital stay are inadequate to cover the cost of the new technology or drug. Generally, medical services and technologies must be new and must demonstrate a substantial clinical improvement over existing services or technologies to receive the additional payment. However, CMS has acknowledged the difficulty antibiotic developers face in demonstrating such substantial clinical improvement due to manufacturers seeking FDA approval for most antibiotics on the basis of noninferiority clinical trials, as described above. To make it easier for antibiotics to qualify for the additional payments, under the revisions to the CMS payment policy beginning in fiscal year 2021, CMS will consider all antibiotics with a QIDP designation from FDA to be “new” for purposes of the add-on payment, and these antibiotics will not have to meet the substantial clinical improvement criteria. In addition, CMS has increased the amount of the temporary add-on payment for qualifying antibiotics. Prior to this change, the add-on payments for qualifying antibiotics were limited to 50 percent of the cost of the drug. Under the new policy, the payment percentage increased to a maximum of 75 percent of the cost of the drug. CMS has specified that two antibiotics are eligible for new technology add- on payments in fiscal year 2020. Increased payment for hospital stays. CMS changed the severity level designation for certain antibiotic resistance-related diagnosis codes, in recognition of the added clinical complexity and cost of treating patients with antibiotic resistance. This change in severity level can result in higher payments to hospitals when treating patients diagnosed with antibiotic resistance, which, according to the Administrator of CMS in an August 2019 blog post, will create “financial flexibility for physicians to prescribe the appropriate new antibiotics.” The Administrator also noted that CMS made this policy change because it recognized that new technology add-on payments are temporary and “further action was needed to realign financial incentives for antibiotics for the long-term.” See appendix III for additional examples of efforts to support antibiotic R&D by these and other federal agencies. Federal Efforts Have Not Fully Incentivized Antibiotic Development, and HHS Lacks a Strategy to Develop New Incentives Experts and antibiotic developers told us that the economic challenges have remained despite the available federal push and pull incentives for antibiotic R&D. Currently available premarket push incentives include grants and awards from NIH and BARDA that fund antibiotic R&D; currently available postmarket pull incentives include the additional market exclusivity available through QIDP designation and Medicare add- on payments for antibiotics. (See fig. 3.) Both of the antibiotic companies that declared bankruptcy in 2019 had received push incentives from BARDA and pull incentives through Medicare New Technology Add-on Payments and the QIDP 5-year extension of market exclusivity. While experts at our meeting and antibiotic developers told us that push incentives have been helpful, they also said push incentives alone are not sufficient to sustain antibiotic development. For example, two antibiotic developers we spoke with explained that push incentives have provided needed funding for conducting R&D, but said that push incentives will not help cover the costs they will incur after their drug reaches the market— for example, to manufacture and market their product. Experts and antibiotic developers have indicated that the effects of the existing pull incentives, QIDP market exclusivity, and Medicare add-on payments on stimulating development of new antibiotics have been limited for the following reasons: QIDP and market exclusivity. As we previously reported, several pharmaceutical companies told us that the market exclusivity incentive may not stimulate the development of new antibiotics, because the extension is unlikely to extend past the typical patent life of a new drug. In addition, a representative from The Pew Charitable Trusts said that, while the passage of the Generating Antibiotic Incentives Now Act initially bolstered private investments in antibiotics, it did not ultimately stabilize the pipeline of antibiotics in development, noting that since then, several large pharmaceutical companies have discontinued their antibiotics R&D programs. Medicare updates to hospital payments. While CMS recently increased new technology add-on payments for certain antibiotics beginning in fiscal year 2020 to help improve access to antibiotics, these payments are limited to antibiotics used to treat Medicare patients. In addition, although Medicare increased the add-on payment amount to up to 75 percent of the estimated costs of qualifying antibiotics in excess of the regular Medicare payment, hospitals could still face costs for providing these drugs that are not covered by the Medicare payment. Furthermore, representatives from an antibiotic company and a biotechnology trade association told us the add-on payments do not directly incentivize hospital pharmacies to purchase the drug, because the add-on payment may not flow back to the pharmacy department’s budget. For these reasons, it remains to be seen whether the Medicare new technology add-on payments to hospitals for inpatient antibiotics will help improve the return on investment for antibiotic developers and further stimulate the antibiotic development pipeline. Similarly, it remains to be seen how CMS’s policy change that provides increased payments for hospital stays when Medicare patients have been diagnosed with certain types of antibiotic-resistant infections will affect hospitals’ use of new antibiotics. In light of the limitation of existing incentives for antibiotic development, experts, federal officials, and antibiotics developers have called for additional postmarket pull incentives to reinvigorate the pipeline of antibiotics under development. For example, PACCARB issued recommendations to the Secretary of HHS in September 2017 and July 2019 for the adoption of pull incentives, calling for the development of market entry rewards and options for plausible business models. In addition TATFAR—of which officials from BARDA, CDC, FDA, and NIH are members—reported that it is critical to develop a pull incentive strategy now to ensure that enough antibiotics are available in the future. Former FDA Commissioner Dr. Scott Gottlieb also stated in 2018 that he was “deeply concerned that without stronger pull incentives that encourage more R&D, we’ll see a far less robust pipeline of products than we need to address antimicrobial resistance.” Eight of the antibiotic developers we interviewed told us they think additional financial incentives are needed. For example, one developer said that sales revenues from antibiotics will never be sufficient to justify R&D investments, and another noted that financial incentives are needed during the first few years after a new antibiotic reaches the market to cover not only these costs, but also to conduct additional clinical trials to help expand the drug’s possible market. Finally, several experts at our expert meeting noted that, without pull incentives, most of the small companies currently developing antibiotics are unlikely to survive, and large pharmaceutical companies will likely continue to exit the antibiotic market. Advisory groups and others have identified multiple options for how postmarket pull incentives could be designed, including market entry rewards—either in the form of lump sum payments or transferable vouchers that could be sold to confer additional market exclusivity to other pharmaceutical drugs—or reimbursement reform, such as licensing arrangements or add-on payments for hospital-administered antibiotics. (See fig. 4.) The four advisory groups whose papers we reviewed each recommended market entry rewards as effective pull incentive options. While Commissioner of the FDA, Dr. Scott Gottlieb proposed an antibiotics licensing arrangement, which he called a subscription model, in a 2018 speech. Views on the utility of reimbursement reform as a pull incentive strategy are mixed. For example, representatives from The Pew Charitable Trusts stated their view that, while CMS’s recent changes to Medicare payment for antibiotics will likely be helpful to some degree, no reimbursement policy on its own would be able to increase antibiotic sales revenues sufficiently to transform the business model for antibiotics. An antibiotic developer we spoke to also told us that reimbursement policies would not be sufficient to support their business model because of low sales volumes for new antibiotics. The developer explained that it can take 2 or 3 years of antibiotic sales to recoup their R&D costs and finance their ongoing business operations, and that while larger pharmaceutical companies can rely on other profitable drugs to offset those costs, they could not because they did not have other drugs on the market. However, a representative from a biotechnology trade association told us that increasing reimbursement could help alleviate some of the economic challenges faced by developers of antibiotics that are already on or about to reach the market while policy makers explore longer-term pull incentive strategies. TATFAR cautioned that simply increasing reimbursement for antibiotics could potentially limit patient access, particularly for patients without health insurance—including those in low-and middle-income countries—and it could incentivize only antibiotics for common types of infections with a large market potential, rather than for rare, yet dangerous, types of pathogens. Advisory groups and others have evaluated potential market entry reward models, taking into consideration factors such as format, value, funding sources, and eligibility criteria. Some have proposed that receipt of a market entry reward should be delinked, fully or partially, from sales revenues—that is, the developer would have to forgo some or all sales revenue as a condition of receiving the reward. Proponents of delinkage believe that separating revenues from antibiotics sales volumes would discourage aggressive sales that could lead to overuse. An expert who attended our meeting later told us that policies to incentivize use of new antibiotics must be balanced with policies to monitor prescribing of new drugs to prevent inappropriate use. Generally, advisory groups stipulate that to maximize the public health benefit, only antibiotics that treat what are deemed to be high priority bacteria should be eligible for a reward. Specific recommendations and conclusions included the following: TATFAR concluded in 2017 that a partially delinked market entry reward of approximately $500 million would be the least disruptive option but noted that additional assessment would be necessary to select the most appropriate model and determine governance and other design elements. PACCARB expressed support for a delinked model, in which a company accepting a market entry reward would be required to forgo marketing activities and profits based on sales volume. In addition, they suggested the establishment of an antibiotic incentive fund supported by an antibiotic usage fee or the sale or auction of transferable exclusivity vouchers as plausible options for financing pull incentives. The Duke University Margolis Center for Health Policy recommended in 2017 a delinked, public-private market entry reward model. This model was comprised of publicly funded market entry rewards for qualifying antibiotics for the first 5 or 6 years, followed by privately funded “value-based” contracts between antibiotic developers and health care payors, in which the payor could agree, for example, to pay a predetermined amount for full access to the antibiotics for a given population. The Duke-Margolis Center proposal did not specify a funding source, but it noted multiple options for consideration, including general government funds, antibiotic use taxes, or the sale of transferable exclusivity vouchers. The European DRIVE-AB project recommended in 2018 an internationally funded, partially delinked market entry reward valued at approximately $1 billion per antibiotic, paid over the course of 5 or more years. Recipients of a market entry reward would be allowed to sell their drug on the private market, but they would agree to certain marketing restrictions to discourage inappropriate use. HHS may need to request authority and appropriations to create and implement certain types of market entry rewards. For example, HHS does not currently have authority to offer transferable exclusivity vouchers to antibiotic developers, since that would require a change in statute. Advisory groups also noted that the various pull incentive approaches would require additional public or private expenditures and offered possible sources of funding. For example, in addition to general fund revenues, PACCARB suggested that pull incentives could be funded through antibiotic usage fees, the auctioning of transferable exclusivity vouchers, or by allowing developers of new antibiotics to earn a transferable exclusivity voucher. The Duke-Margolis Center suggestions included funding market entry rewards through a yearly per-member fee for all health insurance plans. Transferable exclusivity vouchers may not require an independent funding source, because the value of the reward is based on the sale of the voucher to another drug developer. However, vouchers would still increase public and private health care expenditures, because expenditures would likely increase for drugs for which the extra period of exclusivity was purchased due to the delayed entry of lower- priced generics. Finally, reimbursement reform could increase health care expenditures for health care payors, including Medicare and private health insurance carriers. Although PACCARB, TATFAR, and other experts have called for additional postmarket pull incentives to increase the antibiotic pipeline, as of January 2020 HHS has not developed a strategy for creating these incentives. HHS officials told us that the department created an interagency workgroup within HHS in spring 2019 to identify possible pull incentive options, among other things. The recently convened HHS interagency workgroup is a step in the right direction toward exploring options for new antibiotic development incentives. Through this workgroup, HHS has an opportunity to determine which types of postmarket incentives it believes would most effectively incentivize the development of new treatments for antibiotic-resistant infections. However, it is unclear whether the HHS interagency workgroup’s efforts will include consideration of such incentives because, according to HHS officials in January 2020, the interagency workgroup was still considering possible recommendations for HHS leadership and had not produced any specific documents to share with us. The Government Performance and Results Act of 1993 (GPRA) and the GPRA Modernization Act of 2010, which significantly enhanced agencies’ responsibilities under GPRA, include principles for federal agencies to consider related to developing strategies for achieving results, among other principles. We have previously reported that these principles can serve as leading practices for planning at lower levels within agencies, such as individual programs or initiatives. Our past work has shown that strategic frameworks can serve as a basis for guiding policy makers, including congressional decision makers and agency officials, when making decisions about resources, programs and activities, particularly in relation to issues that are national in scope, such as antibiotic development. Developing a strategic framework that outlines new postmarket pull incentives and their key design elements—such as monetary value, eligibility criteria, and guidelines to prevent overuse— would be a first step toward identifying potential authorities and resources that may be needed to create the incentives, and toward determining agency roles for implementation and oversight of the incentives. Until such incentives are developed, more drug companies may exit the antibiotic development sector, and the pipeline of new treatments for antibiotic-resistant infections may continue to decrease. Furthermore, the current significant federal investment in push incentives to support antibiotic R&D will remain a high-risk enterprise, if companies receiving large R&D grants are unable to sustain their business once their treatment reaches the market. Federal Agencies Have Undertaken Several Efforts to Promote the Appropriate Use of Antibiotics, but Key Challenges Remain Federal agencies have undertaken several efforts to promote the appropriate use of antibiotics through stewardship programs and activities. However, four key challenges remain that have limited this progress. Federal Agencies Have Undertaken Several Efforts to Promote the Appropriate Use of Antibiotics through Stewardship Programs To promote the appropriate use of antibiotics across health care settings through antibiotic stewardship programs and activities, federal agencies have undertaken several efforts that aim to reduce inappropriate antibiotic use, reduce health care costs, improve patient outcomes, and combat antibiotic resistance. Selected examples of these efforts are discussed below. (For more detailed information on agencies’ efforts to promote the appropriate use of antibiotics, see app. IV.) Published Requirements for Hospitals, Long-Term Care, and DOD and VA Facilities to Implement Antibiotic Stewardship Programs Federal agencies require certain types of health care facilities to implement antibiotic stewardship programs, as follows: CMS. In September 2019, CMS finalized new health and safety requirements for hospitals and critical access hospitals to implement antibiotic stewardship programs by March 30, 2020, as a condition of their participation in the Medicare and Medicaid programs. Under these requirements, hospitals and critical access hospitals are required, among other things, to implement these programs facility- wide (which includes emergency departments) and to adhere to nationally recognized antibiotic prescribing guidelines. Nearly 3 years prior, CMS published similar requirements for nursing homes and skilled nursing facilities—collectively known as long-term care facilities—to establish antibiotic stewardship programs by December 4, 2017. Experts, including those at our meeting and the PACCARB, credit these requirements with being a powerful lever for promoting the appropriate use of antibiotics; Medicare comprises a significant portion of the nation’s health care expenditures—$741 billion in 2018, covering 59.9 million beneficiaries. DOD. DOD published a policy, effective October 2017, requiring the establishment of antibiotic stewardship programs within its military medical treatment facilities and, one year later, issued guidance for implementation. Among other things, the policy specified that these facilities’ antibiotic stewardship programs include components such as (1) leadership commitment by each facility; (2) accountability; (3) pharmacy expertise, including antibiotic prescribing and use evaluation; (4) implementation of action for change that would demonstrate commitment to the program; and (5) training for clinicians regarding antibiotic resistance and prescribing practices. DOD officials told us that all of these facilities (both inpatient and outpatient) were in different stages of implementing the antibiotic stewardship policy. VA. In January 2019, VA updated its 2014 policy directive for the implementation and maintenance of antibiotic stewardship programs in its health care facilities, which provide both inpatient and outpatient services to veterans. This policy directive includes requirements for its facilities to develop a written policy, conduct an annual evaluation of stewardship activities, ensure that adequate staff and resources are in place, and identify medical and pharmacy personnel as stewardship “champions.” According to department officials, VA has successfully implemented antibiotic stewardship programs in all of its health care facilities. Developed Incentives for Clinicians to Implement Antibiotic Stewardship Activities CMS has developed incentives for eligible clinicians in any type of health care facility to improve antibiotic use and stewardship, as part of the agency’s broader efforts to improve care for Medicare patients. Through the Merit-based Incentive Payment System (MIPS) launched in 2017, CMS offers hundreds of quality measures and nearly 100 “improvement activities” on a wide range of topics—including the appropriate use of antibiotics—on which eligible clinicians can choose to report their performance to the agency. CMS then adjusts payments higher for clinicians who report data and achieve a performance-based, final score above a certain threshold—and penalizes clinicians who do not achieve that threshold with lower payments. Published Guidance on Implementing Antibiotic Stewardship Programs Federal agencies have published guidance for health care facilities on how to implement antibiotic stewardship, as follows: AHRQ. Through a 5-year nationwide project, the AHRQ Safety Program for Improving Antibiotic Use has provided technical assistance and CDC’s guidance to hospitals, long-term care settings, and physicians’ offices to promote implementation of antibiotic stewardship activities and help clinicians select optimal antibiotic treatment regimens. In December 2018, AHRQ completed implementation of this guidance in more than 400 hospitals, which included six DOD facilities and 79 critical access hospitals, according to AHRQ officials. CDC. Since 2014, CDC has published a series of guidance documents—called the Core Elements of Antibiotic Stewardship (Core Elements)—to promote the appropriate use of antibiotics in health care. The Core Elements are tailored to hospitals, nursing homes, outpatient settings, small and critical access hospitals, and low- and middle-income countries with limited resources. Common elements in these guidance documents include (1) leadership commitment, (2) implementation of policies and interventions to improve antibiotic use, (3) tracking and reporting antibiotic use, and (4) education to providers on appropriate antibiotic use. Expanded the Collection of Antibiotic Use Data For more information on MIPS, see GAO, Health Care Quality: HHS Should Set Priorities and Comprehensively Plan Its Efforts to Better Align Health Quality Measures, GAO-17-5 (Washington, D.C.: Oct. 13, 2016) and Medicare: Small and Rural Practices’ Experiences in Previous Programs and Expected Performance in the Merit-based Incentive Payment System, GAO-18-428 (Washington, D.C.: May 31, 2018). other sources. In particular, CDC has focused its efforts to expand antibiotic use data collection from hospitals, where an estimated one in two patients receives an antibiotic for at least one day during an average hospital stay. CDC launched its AU Option in 2011 as a voluntary, electronic reporting tool added on to the pre-existing NHSN. The AU Option allows the nation’s 6,849 hospitals that are already reporting to the NHSN to submit their antibiotic use data in a standardized format. CDC then aggregates such data to calculate national benchmarks and allows hospitals to compare their actual antibiotic use against those benchmarks. In addition, CDC has periodically conducted prevalence surveys through the EIP to gather data on health care-associated infections and antibiotic use in about 200 hospitals and 161 nursing homes in 10 states. With regard to outpatient settings, CDC has acquired, through a proprietary source, 8 years of pharmacy data on antibiotic prescriptions since 2011, which the agency is using to better characterize patterns in outpatient prescribing and to develop targeted interventions for high-prescribing areas. Developed Antibiotic Stewardship Training for Various Health Care Settings Federal agencies have developed training on antibiotic stewardship, as follows: CDC. In 2018, CDC launched a free, online training course for various types of clinicians—including physicians, dentists, pharmacists, physician assistants, and nurses—to inform them about proper antibiotic prescribing and strategies for communicating with patients. Clinicians can receive credit for partial completion (at least 50 percent) or full completion of this training as improvement activities under MIPS in 2019. CMS. CMS has provided training, technical assistance, and other learning opportunities to more than 4,000 hospitals, 2,400 nursing homes, and 7,600 outpatient settings on best practices for antibiotic stewardship and guidance on C. difficile prevention. In addition, CMS and CDC have developed and launched free, online training to help nursing homes implement antibiotic stewardship and prevent and manage C. difficile infections. DOD and VA. These departments have also offered antibiotic stewardship training to their health care facilities through webinars, workshops, or briefings. Funded Research Federal agencies have funded research on antibiotic stewardship, as follows: AHRQ. Since 2015, AHRQ has increased its support for research to develop improved methods to combat antibiotic resistance and promote antibiotic stewardship, including through grants for research that will total more than $57 million, according to AHRQ officials. This research includes studies on the role of diagnostic tools in improving antibiotic use and reducing antibiotic resistance. AHRQ has also published numerous research studies on antibiotic or antimicrobial stewardship that the agency funded or authored. CDC. CDC supports research to identify, develop, and implement practices to stop the spread of resistance and to promote appropriate use of antibiotics in health care. CDC also supports research to fill gaps in knowledge related to aspects of antibiotic use and resistance that have public health impact. According to agency officials, CDC has provided approximately $110 million since 2016 to support this research through cooperative agreements and contracts. Continued National Public Awareness Campaign In 2017, CDC revised a national campaign to promote public awareness about appropriate antibiotic use. The campaign, called “Be Antibiotics Aware: Smart Use, Best Care,” is aimed at both health care providers and the general public and refines the message from CDC’s earlier campaign (“Get Smart: Know When Antibiotics Work”). Collaborated Internationally HHS’s Office of Global Affairs has collaborated with other countries, including those participating in the TATFAR program, to promote the appropriate use of antibiotics internationally. In addition, CDC and the Office of Global Affairs launched the Antimicrobial Resistance Challenge at the United Nations General Assembly in September 2018 to catalyze global action against antibiotic resistance. A year later, CDC announced this challenge had resulted in nearly 350 commitments from government health officials, pharmaceutical and health insurance companies, and others from 33 countries to make formal commitments that further the progress against antimicrobial resistance, such as by improving appropriate antibiotic use. Four Key Challenges Have Limited Federal Efforts to Promote the Appropriate Use of Antibiotics We identified four key challenges that have limited progress in federal efforts to promote the appropriate use of antibiotics, based on our analysis of documents, interviews with agency officials and experts, and other information. First, federal requirements for antibiotic stewardship programs apply only to certain types of health care facilities, and federal incentives for clinicians to adopt antibiotic stewardship activities are optional, limiting implementation of antibiotic stewardship across the health care spectrum. Second, CDC faces challenges in collecting complete antibiotic use data, limiting the agency’s ability to monitor and improve antibiotic use. Third, the CARB Task Force has not identified and reported on agencies’ plans to address the challenges related to expanding antibiotic stewardship programs and antibiotic use data collection across health care settings, so these plans are not publicly known. Fourth, antibiotic stewardship training for health care providers may have limited success in improving antibiotic prescribing behavior, and federal agencies indicate that it is challenging to evaluate the effectiveness of such training. Federal Requirements and Incentives Are Limited Federal requirements for antibiotic stewardship programs are limited to certain types of health care facilities, and federal incentives for antibiotic stewardship activities are optional and limited to eligible Medicare clinicians, such as physicians. Federal requirements for antibiotic stewardship programs are limited to certain types of health care facilities. As previously noted, federal requirements for antibiotic stewardship programs are currently limited to hospitals and critical access hospitals, long-term care facilities such as nursing homes, and DOD and VA health care facilities. However, CMS has not yet developed requirements for ambulatory surgery centers or dialysis centers to implement antibiotic stewardship programs, which the National Action Plan called for being implemented by March 2018. CMS officials told us that the agency would develop those requirements once the rule for hospitals and critical access hospitals—which was delayed—was finalized. In addition, CMS’s health and safety requirements do not extend to other types of outpatient settings—such as physicians’ offices, retail clinics, and urgent care centers—where inappropriate antibiotic use has been found to be high. In the absence of regulatory levers, CDC and AHRQ encourage those types of facilities to establish antibiotic stewardship programs on a voluntary basis. Experts, including those at our meeting, indicate that expansion of antibiotic stewardship across the health care spectrum is likely to remain limited without additional federal requirements or other meaningful incentives—thus hindering the nation from fully achieving the benefits of appropriate antibiotic use. Such benefits include better patient outcomes, lower health care costs, and slower growth of antibiotic resistance. CMS incentives for clinicians to improve antibiotic use are optional, and implementation has been limited. The MIPS program’s effect on incentivizing appropriate use of antibiotics is limited, in part, because the incentives are available only to clinicians who meet MIPS eligibility criteria and because eligible clinicians can choose not to report data to CMS. In addition, participating clinicians have a wide range and number of quality measures and improvement activities, beyond those related to antibiotics, from which the clinicians can choose to report data to CMS to meet program requirements; thus, the likelihood that clinicians will choose to report on antibiotics- related measures or activities may remain low. For example, in 2017, MIPS-eligible clinicians were generally required to select and submit data to CMS on six out of 271 available quality measures; we identified nine of those measures as being related to antibiotics. MIPS-eligible clinicians were also generally required to select and submit data that year for up to four out of 93 available improvement activities; we identified one such activity as being related to antibiotics. Our analysis of CMS data on MIPS participation in 2017, the program’s first performance year and the most recently available data, indicates that implementation of the antibiotics-related quality measures and improvement activities was limited. According to a CMS report, a total of 1,057,824 clinicians were eligible for MIPS in 2017, of which 1,006,319 clinicians, or 95 percent, reported data. Based on our analysis of data contained in the CMS report’s appendix, the number of 2017 MIPS-participating clinicians who reported to CMS on the nine antibiotics-related quality measures ranged from 844 clinicians to 33,631 clinicians; the measure on appropriate treatment for children with an upper respiratory infection was the most reported antibiotics-related measure. By contrast, the most frequently reported quality measures overall in 2017 were controlling high blood pressure (510,723 clinicians), preventive care and screening for tobacco use (492,357), and breast cancer screening (473,819). CMS’s data also show that for the 2017 MIPS improvement activities, 47,645 of the 1,006,319 participating clinicians reported on the one improvement activity related to antibiotics that year: implementation of an antibiotic stewardship program. Specifically, this activity referred to implementation of an antibiotic stewardship program that measured the appropriate use of antibiotics for several different conditions (upper respiratory infections in children, pharyngitis, and bronchitis in adults), according to clinical guidelines for diagnostics and therapeutics. CDC Faces Challenges in Collecting Complete Antibiotic Use Data, Limiting the Agency’s Ability to Monitor and Improve Appropriate Use CDC’s ability to monitor and improve appropriate antibiotic use is limited by challenges it faces in collecting complete antibiotic use data across health care settings. According to CDC, experts we interviewed, and documents we reviewed, more data are needed to identify the extent of antibiotic use, including inappropriate use. In turn, CDC and experts say that more antibiotic use data would enable health care providers, federal agencies, and others to identify and target areas for improvement, track results over time, and adjust antibiotic stewardship activities as needed. We have also previously reported that monitoring antibiotic use over time in both inpatient and outpatient settings is important for understanding patterns in antibiotic resistance and for targeting stewardship activities. In addition, WHO notes that data on global antibiotic use is essential for obtaining a comprehensive picture of antibiotic resistance and for identifying areas where actions are needed. Despite progress in collecting antibiotic use data (as previously discussed), CDC faces several challenges in its efforts to collect complete antibiotic use data. For example, health care providers across various inpatient and outpatient settings do not record such data in one centralized, electronic database. In addition, CDC officials told us that there are no uniform requirements at the federal level (with the exception of DOD and VA hospitals) for providers to report their antibiotic use data to a centralized database such as the NHSN AU Option, and, according to CDC officials and experts we interviewed, data collection can be costly for CDC and health care providers. Because of these and other challenges, CDC relies on data voluntarily reported by hospitals through the AU Option, and the agency collects its own data or purchases proprietary pharmacy data to estimate antibiotic use—and, to some degree, to assess appropriateness of use—across health care settings. However, these data are incomplete owing to several limitations, as described by type of setting below. Hospitals. Our analysis of CDC data shows that although the number of hospitals participating in the AU Option has gradually risen since its launch in 2011, participation remains limited, with 1,561, or 23 percent, of the 6,849 eligible hospitals reporting at least one month of antibiotic use data as of January 1, 2020. (See fig. 5 for a map showing the percentage of U.S. hospitals reporting antibiotic use data to the AU Option, by state, plus the District of Columbia and Puerto Rico, as of August 2019.) While CDC officials told us they considered this level of participation to be an accomplishment given that participation is voluntary, the National Action Plan set 95 percent participation in the AU Option by 2020 as a significant outcome to support the plan’s goal to strengthen national surveillance efforts to combat resistance. Experts, including those at our meeting, cite multiple challenges that CDC faces in collecting hospitals’ antibiotic use data through the AU Option. For example, The Pew Charitable Trusts has stated that current, voluntary data are limited and that mandatory reporting would provide the data needed to establish a more accurate baseline of antibiotic use, identify stewardship interventions that would be most effective, and measure progress toward reducing inappropriate prescribing. An expert who attended our meeting later suggested that CMS could implement a pay-for-reporting program to incentivize hospitals to report data to the AU Option, and that the program could transition to a pay-for-performance program over time. In addition, experts we interviewed told us that a participating hospital must be willing to spend as much as tens of thousands of dollars for a vendor to customize software for their electronic health record systems to use the AU Option, in addition to investing time training staff on how to use it. CDC officials also told us that the agency lacks the authority to require hospitals to report their antibiotic use data, and that there is currently no federal funding available to assist hospitals with the investment needed to participate in the AU Option. Furthermore, hospitals’ voluntary participation in the AU Option may remain limited until CDC’s benchmark measures are adequately risk- adjusted for different locations and patient populations. For example, one expert we interviewed said that because the AU Option currently aggregates data on the volume of antibiotics used without adequate risk adjustment, a hospital with a patient population that might warrant higher use of antibiotics may be reluctant to report its antibiotic use data to avoid looking like an unnecessarily high prescriber. Regarding another data source for antibiotic use in hospitals, CDC’s EIP provides more granular data at the patient level that allows CDC to assess the appropriateness of antibiotic use. However, CDC officials told us that the agency has been unable to repeat its hospital prevalence survey since 2015 due to insufficient resources (the next survey is expected in 2020) and that the survey encompasses a limited number of hospitals, patients, and states. Nursing homes. According to CDC, nursing homes may be the most challenging health care setting from which the agency collects antibiotic use data; CDC officials stated that this is because electronic health record systems, from which data could be easily accessed, are less common in nursing homes. In addition, CDC officials stated that the agency’s collection of antibiotic use data through the EIP nursing homes prevalence survey has been limited in scope and frequency due to insufficient resources. Outpatient settings. Collecting data for outpatient settings, such as retail pharmacies, is also challenging. For example, CDC officials stated that one proprietary source from which CDC purchases data reflects the volume of pharmacy antibiotic prescriptions, but the data do not contain diagnostic information, preventing the agency from evaluating the appropriateness of those prescriptions. Other CDC or proprietary data sources from which the agency collects or purchases antibiotic use data are limited by the frequency with which those sources release such data, the age range of patients included in the data (i.e., whether they are over or under 65 years), or other characteristics. As previously noted, approximately 85 to 95 percent of the nation’s antibiotic use, by volume, occurred in outpatient settings from 2010 through 2015. The CARB Task Force Has Not Identified Plans to Address Challenges Related to Expanding Stewardship Programs and Antibiotic Use Data Collection The National Action Plan calls for strengthening antibiotic stewardship and for the timely reporting of antibiotic use data across health care settings. Executive Order No. 13676, as previously noted, directs the CARB Task Force to provide annual updates to the President on federal government actions to combat antibiotic resistance, including progress made in implementing the National Action Plan and plans for addressing any barriers preventing its full implementation. These annual updates are to include specific goals, milestones, and metrics for proposed actions and recommendations, taking into consideration federal resources. However, in its progress reports covering the first four years of the National Action Plan’s implementation—which were provided to the President and the public—the CARB Task Force has not identified plans to address barriers that agencies face in expanding antibiotic stewardship programs across health care settings. For example, the task force did not include in the progress reports CMS’s plans to address barriers to expanding its requirements for antibiotic stewardship programs in hospitals, which were delayed, or in certain other types of health care facilities. In addition, in its progress reports to date, the CARB Task Force has not identified plans to address the barriers to expanding the collection of antibiotic use data across health care settings. For example, the task force did not include in the progress reports CDC’s plans to address barriers to achieving the significant outcome of 95 percent of eligible hospitals participating in the AU Option by 2020, although participation was only 23 percent as of January 1, 2020. The CARB Task Force coordinators said, in response to our inquiries during this review, that the task force intends to identify agencies’ plans for addressing barriers in the Year 5 progress report to be published in fall 2020. However, the coordinators also stated that the progress reports to date have not identified plans to address barriers largely because the task force focused on reporting the agencies’ accomplishments in implementing the National Action Plan. Until the CARB Task Force identifies and reports on agencies’ plans to address barriers related to the expansion of antibiotic stewardship programs and the collection of antibiotic use data across health care settings to the extent feasible, the federal government will not have reasonable assurance that it is fully implementing the National Action Plan and addressing antibiotic resistance. Antibiotic Stewardship Training May Have Limited Success in Improving Prescribing Behavior While training is recognized as one component of an antibiotic stewardship program, such training may have limited success in improving antibiotic prescribing behavior, and federal agencies indicate that it is challenging to evaluate the training’s effectiveness. CDC officials and experts say that inappropriate antibiotic use could be improved through stewardship training, but it is challenging because antibiotic prescribing behavior is driven by multiple factors and can be difficult to change. For example, a PACCARB report stated that prescribers often feel pressure to prescribe antibiotics—even when antibiotics may not be warranted—because of their perception that a patient is demanding such a prescription, or a patient’s actual demand. In addition, CDC notes that antibiotics are frequently prescribed for respiratory conditions most commonly caused by viruses such as the common cold, against which antibiotics are ineffective. Other factors that drive antibiotic prescribing behavior, as cited by experts, include habit, which may stem from what physicians and other prescribers learn during their residencies or observe in the workplace; the time it takes to explain to a patient why an antibiotic is inappropriate; and “decision fatigue” caused by tiredness or hunger. (See table 4 for examples of factors that drive or deter antibiotic prescribing behavior.) Nevertheless, federal agencies plan to evaluate the effectiveness of their antibiotic stewardship training programs to some extent, although the National Action Plan does not require the agencies to do so. For example, CDC officials told us that their online training course for various types of clinicians allows participants to fill out an evaluation that includes questions about whether the participant will be able to apply knowledge gained from the course, which the agency will use to refine and update the course. In addition, for the antibiotic stewardship training for nursing homes that CDC and CMS jointly developed, CDC officials told us that participants will be asked 6 months after the training whether participants implemented stewardship practices—and whether there have been reductions in antibiotic use—as a result of the training. However, CMS, DOD, and VA officials noted that it is difficult to isolate and measure the effectiveness of antibiotic stewardship training specifically on antibiotic prescribing behavior—compared to other, concurrent federal efforts, such as requirements and guidance to promote appropriate antibiotic use. For example, DOD officials told us that their department has looked at antibiotic use data from DOD health care facilities as a “surrogate” to evaluate whether antibiotic stewardship in general has been effective—but noted that is an imperfect measure since there are many factors that affect antibiotic prescribing behavior, and training is only one of several interventions aimed at reducing inappropriate antibiotic use. Conclusions Antibiotic resistance has been characterized as one of the greatest public health threats the world faces. A concerted effort involving coordination of multiple stakeholders and countries and across health fields is critical to helping ensure that bacterial infections remain treatable. Steps by federal agencies to expand surveillance, facilitate the development and use of new diagnostic tests, fund R&D for the development of new treatments, and issue requirements and guidance for antibiotic stewardship programs are important efforts toward addressing the problem of antibiotic resistance and implementing the National Action Plan. Significant challenges to conducting surveillance remain. For example, CDC has not determined the participation rates or appropriate distribution of participating hospitals needed by the voluntary antibiotic-resistance reporting option to achieve CDC’s goal of conducting regional and national assessments of resistance. By taking steps to determine the participation rates and distribution needed for this option, CDC would have more reasonable assurance that it can achieve its goal. CDC classified gonorrhea as one of the most urgent resistant threats in the nation, but collects limited specimens—representing an estimated 1 to 2 percent of the reported cases in the United States—for GISP, its primary surveillance system for resistant gonorrhea. However, CDC has not fully evaluated the representativeness of the trends identified by this surveillance system. By evaluating GISP to ensure that it includes measures of its representativeness, such as comparing the trends in the sample population with those in the overall U.S. population, using specially designed studies if needed, CDC would have better assurance that the trends detected in GISP accurately reflect the characteristics of the health-related outcome the system is designed to monitor. Further, neither the 2013 nor the 2019 Threats Reports provided quantitative measures of uncertainty for CDC’s estimates of morbidity and mortality resulting from antibiotic-resistant infections. Providing such measures, such as standard errors or confidence intervals, as appropriate, in its Threats Reports would help CDC and others compare information within and across reporting efforts, and draw appropriate conclusions about the characteristics of antibiotic resistance in the United States, including limitations associated with reported findings and conclusions. Finally, there has been a 6-year interval between CDC’s reports on antibiotic resistance threats. By developing a plan for more frequent dissemination of consolidated reporting on priority pathogens at regular intervals, CDC would have more timely trend data and other information necessary for users of the data, including policymakers, to prioritize, plan, implement, and evaluate public health actions to address antibiotic resistance. HHS has funded some studies to assess whether certain tests for antibiotic resistance lead to improved clinical outcomes, including more effective treatment for patients or more judicious use of antibiotics. However, HHS agencies that are in a position to conduct or fund such studies have not identified leadership, roles, and responsibilities to help further such efforts. By taking steps to identify leadership, roles, and responsibilities, agencies could more effectively address the need for clinical outcomes studies, potentially increasing test use, improving patient care, and enhancing stewardship efforts. In addition, for its part, FDA has not regularly monitored tests for antibiotic resistance to assess breakpoint updates or evaluated any effects of using tests for antibiotic resistance with out-of-date breakpoints. By regularly monitoring and evaluating FDA-authorized tests that rely on breakpoints, FDA would be able to determine whether test manufacturers are updating breakpoints as needed and help ensure that patient care and infection control efforts are effective. While government push incentives to support antibiotic R&D have been helpful, experts and antibiotic developers have indicated that push incentives alone are not sufficient to sustain antibiotic development. PACCARB, TATFAR, and other experts have called for additional postmarket pull incentives to increase the antibiotic pipeline, but HHS does not have a strategy for doing so. Developing a strategic framework that outlines key design elements of new incentives would be a first step toward identifying potential authorities and resources that may be needed and determining agency roles for implementation and oversight of the incentives. Until such incentives are developed, more drug companies may exit the antibiotic development sector, and the pipeline of new treatments may continue to decrease. Finally, in its progress reports covering the first four years of the National Action Plan’s implementation, the CARB Task Force did not identify plans, as required by the Executive Order, to address barriers that agencies face in fully implementing the National Action Plan, such as expanding (1) a CDC program designed to strengthen the U.S. response to resistant gonorrhea; (2) antibiotic stewardship programs across health care settings; and (3) antibiotic use data collection, to the extent feasible. Without identifying plans to address these and other challenges, the federal government cannot assure that the country is prepared to overcome the urgent health consequences of antibiotic resistance. Until the CARB Task Force, which is coordinated by HHS officials, identifies and reports on agencies’ plans to address barriers preventing full implementation of the National Action Plan, the federal government will not have reasonable assurance that it is fully implementing the National Action Plan and addressing antibiotic resistance. Recommendations for Executive Action We are making a total of eight recommendations, including four to CDC, three to HHS, and one to FDA. Specifically: The Director of CDC should take steps to determine participation rates and distribution needed in the AR Option of the National Healthcare Safety Network for conducting regional and national assessments of antibiotic resistance of public health importance. (Recommendation 1) The Director of CDC should ensure that CDC’s evaluation of its surveillance system for antibiotic-resistant gonorrhea includes measures of its representativeness, such as comparison of the trends in the sample population with those in the overall U.S. population, using specially designed studies if needed. (Recommendation 2) The Director of CDC should provide information on uncertainties for antibiotic resistance estimates in its consolidated Threats Reports, including standard errors or confidence intervals, as appropriate. (Recommendation 3) The Director of CDC should develop a plan for timely, consolidated reports of antibiotic resistance in priority pathogens at regular intervals. (Recommendation 4) The Secretary of HHS should identify leadership and clarify roles and responsibilities among HHS agencies to assess the clinical outcomes of diagnostic testing for identifying antibiotic-resistant bacteria. (Recommendation 5) The Commissioner of FDA should direct the Center for Devices and Radiological Health to conduct additional monitoring and evaluation of the status of FDA-authorized tests that rely on breakpoints, on a regular basis, to determine whether test manufacturers are updating breakpoints, seeking additional resources as needed. (Recommendation 6) The Secretary of HHS should develop a strategic framework to further incentivize the development of new treatments for antibiotic-resistant infections, including through the use of postmarket financial incentives, and, if appropriate, make recommendations to Congress for necessary authority. (Recommendation 7) The Secretary of HHS should direct the CARB Task Force to include in its annual updates to the President plans for addressing any barriers preventing full implementation of the National Action Plan and, as appropriate, make recommendations for new or modified actions. Specifically, the CARB Task Force should identify plans to address barriers, such as those related to expanding (1) a CDC program designed to strengthen the U.S. response to resistant gonorrhea; (2) antibiotic stewardship programs across health care settings; and (3) antibiotic use data collection across health care settings, to the extent feasible. (Recommendation 8) Agency Comments and Our Evaluation We provided a draft of this report to DOD, VA, and HHS for review and comment. DOD and VA did not provide formal comments but generally agreed with our report. In its comments, reproduced in appendix V, HHS generally concurred with our findings and seven of our recommendations, and did not concur with one of our recommendations, as discussed below. HHS identified several actions it intends to take to address our recommendations. DOD and HHS also provided technical comments, which we incorporated as appropriate. In response to our first recommendation, HHS concurred and CDC stated it is working with public health partners to promote the voluntary use of the AR Option, providing technical support to states that may be considering a state or local mandate to require AR and AU reporting, and developing pilot programs to assess AR Option data and other data sources for certain types of antibiotic resistance. While these actions are helpful, we believe taking additional steps, such as determining goals for participation rates and distribution for AR Option reporting, would give CDC more reasonable assurance that hit can conduct regional and national assessments of resistance. In response to our second recommendation, HHS concurred and CDC stated it is taking additional efforts to examine the representativeness of data collected through its primary surveillance system for resistant gonorrhea, including working to develop laboratory methods to reduce dependence on cultured isolates. CDC stated that steps to refine and improve collection of resistant gonorrhea data require additional resources. We believe that CDC requesting such resources would help ensure that such data are representative of the overall U.S. population. HHS generally concurred with our third recommendation. CDC stated it feels that it is critical to publish the data after peer review and then plans to link the publications back to online resources of the 2019 Threats Report. We believe that peer-reviewed publication is important, but it is also important for CDC to take additional steps to establish and report uncertainties for the national estimates or summary data that would help CDC and others draw appropriate conclusions about the characteristics of antibiotic resistance in the United States. In response to our fourth recommendation, HHS concurred and CDC stated it has plans to update its enterprise-wide AR Threats Report every three years, and that it also issues regular reports on specific groups of pathogens. In response to our fifth recommendation, HHS concurred and stated that the CARB Task Force leadership will work with relevant HHS agencies to clarify roles and responsibilities and identify leadership, if appropriate, for supporting research on clinical outcomes delated to diagnostic tests. HHS concurred with our sixth recommendation, and FDA concurred with conducting additional monitoring and evaluation of tests relying on breakpoints when FDA identifies or recognizes new breakpoints. FDA stated that it has taken major steps to help address challenges associated with updating such tests to reflect the most current breakpoints. We believe that in addition to these steps, monitoring and evaluation of current FDA-authorized tests that may still be using out-of- date breakpoints will enhance FDA’s ability to provide assurance that patient care and infection control efforts are effective. HHS did not concur with our seventh recommendation that HHS should develop a strategic framework to further incentivize the development of new treatments for antibiotic-resistant infections, including through the use of postmarket financial incentives. HHS noted that, while it agrees that additional incentives are needed to address the limited pipeline for novel and innovative treatments to combat antibiotic resistance, it is still conducting analyses to understand whether postmarket incentives should be included as a component of its forthcoming strategic framework to further incentivize the development of new treatments. However, HHS did not specify when its framework would be released. We support HHS’s efforts to develop such a framework, as this is a complex issue with multiple factors to consider. However, we believe our recommendation is still warranted. Antibiotic resistance is one of the greatest global public health threats, and experts, including the WHO, have warned that the pipeline of new antibiotics in development is insufficient to combat the threat. Without an adequate arsenal of treatments, we are likely to see increasing mortality caused by these deadly infections. As we reported, experts, advisory groups, federal officials, and antibiotic developers have all called for additional postmarket incentives to reinvigorate the pipeline of antibiotics under development. The current significant federal investment in push incentives to support antibiotic R&D is helpful but will ultimately be ineffective if companies receiving this investment are unable to sustain their business once their treatment reaches the market. Therefore, we maintain that it is important that HHS not delay the development of a strategic framework that includes postmarket incentives, which is just an initial step toward the creation of these incentives. Until additional postmarket incentives are developed, more drug companies may exit the antibiotic development sector, and the pipeline of new treatments for antibiotic-resistant infections may continue to decrease. In response to our eighth recommendation, HHS concurred and stated that beginning in 2020 and continuing annually thereafter, the CARB Task Force’s progress reports will include discussion of any barriers preventing full implementation of the National Action Plan, including, as appropriate, barriers that GAO has identified. We emphasize that the CARB Task Force should also identify plans to address such barriers—and, as appropriate, make recommendations for new or modified actions—in future progress reports, in accordance with Executive Order No. 13676. As agreed with your offices, unless you publicly announce the contents of this report earlier, we plan no further distribution until 30 days from the report date. At that time, we will send copies to appropriate congressional committees; the Secretaries of DOD, HHS, and VA; and other interested parties. In addition, the report will be available at no charge on the GAO website at http://www.gao.gov. If you or your staff have any questions about this report, please contact us at (202) 512-6888 or personst@gao.gov, or (202) 512-7114 or deniganmacauleym@gao.gov. Contact points for our Offices of Congressional Relations and Public Affairs may be found on the last page of this report. GAO staff who made key contributions to this report are listed in appendix VI. Appendix I: Objectives, Scope, and Methodology This report examines: (1) the Centers for Disease Control and Prevention’s (CDC) efforts to address surveillance of antibiotic resistance and any challenges to these efforts; (2) federal efforts to advance the development and use of diagnostic tests for identification and characterization of resistant bacteria and to address barriers to the development of diagnostic tests; (3) challenges to developing new treatments for antibiotic-resistant infections and federal efforts to address the challenges; and (4) federal efforts to promote the appropriate use of antibiotics and any challenges that remain. We focused our review primarily on agency actions since 2015, when the National Action Plan for Combating Antibiotic-Resistant Bacteria (National Action Plan) was published. We also focused our review on human health, as we have reported on federal efforts to address the use of antibiotics in food animals and recommended actions to improve these efforts for more than 20 years. Additionally, we focused our review on antibiotic-resistant bacteria. We generally excluded federal efforts related to infection prevention and control in human health care, on which we have previously reported. To address all four objectives, we reviewed relevant agency reports and documents, such as CDC’s report, Antibiotic Resistance Threats in the United States, 2013 (2013 Threats Report); conducted interviews with officials from federal agencies, experts, and stakeholder organizations; and we reviewed relevant literature, policy papers, and GAO reports. We interviewed officials from federal agencies responsible for implementing the aspects of the National Action Plan related to our research objectives: the Department of Health and Human Services’ (HHS) Office of the Assistant Secretary for Planning and Evaluation, the Biomedical Advanced Research and Development Authority (BARDA), CDC, the Centers for Medicare & Medicaid Services (CMS), the Food and Drug Administration (FDA), the National Institutes of Health (NIH), and the Office of Global Affairs; as well as the Department of Defense (DOD) and the Department of Veterans Affairs. We also interviewed experts and representatives from organizations involved in public health and epidemiology, infectious diseases and microbiology, antibiotic research and development (R&D), antibiotic stewardship, and other issues relating to antibiotic resistance. Because antibiotic resistance is a global problem, we also interviewed officials from the World Health Organization (WHO), the European Centre for Disease Prevention and Control, the European Medicines Agency, the Wellcome Trust, Public Health England, and the Surveillance and Epidemiology of Drug-Resistant Infections Consortium about various aspects of our review; and we reviewed relevant documents from these entities. We identified experts and organizations through literature and other documents we reviewed and through referrals from agency officials and other experts we interviewed. In addition, we attended several meetings and reviewed summaries of meetings held by the Presidential Advisory Council on Combating Antibiotic-Resistant Bacteria (PACCARB). Furthermore, we attended two conferences related to antibiotic resistance: the World Anti-Microbial Resistance Congress and the Gordon Research Conference on chemical and biological threat defense, the latter of which had a session devoted to antibiotics and antibiotic resistance. For each of our objectives, we identified and reported on actions taken by federal agencies and key challenges that the agencies face in addressing antibiotic resistance. We evaluated the actions taken by federal agencies against relevant criteria, as applicable. In addition, in September 2018, we convened a meeting of experts in antibiotic resistance epidemiology, diagnostic testing, antibiotic development, and antibiotic stewardship. This meeting of experts was planned and convened with the assistance of the National Academy of Sciences to better ensure that a breadth of expertise was brought to bear in its preparation; however, all final decisions regarding meeting substance and expert participation are the responsibility of GAO. Any conclusions and recommendations in GAO reports are solely those of the GAO. The Board on Population Health and Public Health Practice within the National Academy of Sciences solicited expert nominations from academia, public health laboratories, industry, and other organizations working in topics relating to antibiotic resistance. From their list of 51 nominees, and additional nominees we independently identified, we convened a meeting of 18 experts selected for their knowledge and expertise related to antibiotic resistance epidemiology, diagnostic testing, antibiotic development, and antibiotic stewardship. Eleven of the 18 experts who participated in our meeting also reviewed and provided comments on a draft of our report. We refer to such experts in this report as “experts at our meeting;” appendix II contains a list of the expert participants. To examine CDC’s efforts to address surveillance for antibiotic resistance and any challenges to these efforts, we reviewed documentation and conducted interviews with agency officials and other key stakeholders on each of the surveillance systems across CDC that track antibiotic resistance and reviewed CDC’s 2013 Threats Report and CDC’s Antibiotic Resistance Threats in the United States, 2019 data. We further focused our review on the 17 priority disease-causing bacteria listed in CDC’s 2013 Threats Report. The CDC surveillance systems included: Antibiotic Resistance Laboratory Network Emerging Infections Program (EIP) Gonococcal Isolate Surveillance Program (GISP) National Antimicrobial Resistance Monitoring System (NARMS) National Healthcare Safety Network (NHSN) National Notifiable Diseases Surveillance System National Tuberculosis Surveillance System For NHSN, we also assessed health care facility participation data by state and territory. We assessed the reliability of these data by reviewing them for any outliers or anomalies and by inquiring with agency officials about their source and any known reliability issues. We determined that these data were sufficiently reliable for assessing facility participation rates by U.S. state and territory. Stakeholder organizations we interviewed represented state and territorial epidemiologists and other public health officials (the Council of State and Territorial Epidemiologists and the Association of State and Territorial Health Officials) and an international consortium to address challenges in surveillance of antibiotic resistance (the Surveillance and Epidemiology of Drug-resistant Infections Consortium). We also reviewed reports on antibiotic resistance surveillance challenges from the Public Health Informatics Task Force and the Antibiotic Resistance Surveillance Task Force. We also reviewed documents from WHO’s global surveillance system and interviewed WHO and CDC officials to identify challenges that limit CDC’s ability to assess threats from abroad. We evaluated challenges and steps CDC has taken against CDC’s “Updated Guidelines for Evaluating Public Health Surveillance Systems;” Standards for Internal Control in the Federal Government; prior GAO work; the Government Performance and Results Act of 1993 (GPRA) and the GPRA Modernization Act of 2010; the Office of Management and Budget Circular No. A-11 and Standards and Guidelines for Statistical Surveys; relevant National Action Plan objectives, aims, and milestones; and Executive Order No. 13676, September 2014. To examine federal efforts to advance the development and use of diagnostic tests, we also interviewed representatives from a nongeneralizable selection of six diagnostic test manufacturers to identify challenges they face in developing tests for antibiotic resistance and challenges in increasing user adoption of their tests. We further focused our review on the 17 priority disease-causing bacteria listed in CDC’s 2013 Threats Report. The six manufacturers we interviewed were Accelerate Diagnostics, Beckman Coulter, BioFire and its parent company, BioMerieux, Bruker, Cepheid, and Roche Diagnostics. We identified these manufacturers by compiling a list based on previous work we conducted, interviews with select experts, and internet search. We selected six manufacturers that were identified by more than one source while encompassing different types of tests (culture and genotypic). We limited our scope to FDA-authorized tests—that is, tests that have been reviewed and cleared by FDA for marketing in the United States—that can identify resistance in at least one type of bacteria categorized as priority bacteria in CDC’s 2013 Threats Report. Some of these tests are called antibiotic susceptibility tests, but we refer to the entire class of such tests as “tests.” We included in our scope tests that can differentiate between viral and bacterial infection because these types of tests are included in the National Action Plan. We evaluated the actions taken by federal agencies against the Standards for Internal Control in the Federal Government, relevant National Action Plan objectives, aims, and milestones under Goal 3, and relevant sections in the PACCARB Recommendations for Incentivizing the Development of Vaccines, Diagnostics, and Therapeutics to Combat Antibiotic Resistance. We also evaluated federal agency actions against the “leadership” and “clarity of roles and responsibilities” leading practices from GAO’s Managing for Results: Key Considerations for Implementing Interagency Collaborative Mechanisms. We focused on these key practices when there was a lack of specifically assigned roles in either the National Action Plan or the PACCARB report for key activities. To identify challenges to developing new treatments for antibiotic- resistant infections and examine federal efforts to address these challenges, we also interviewed 11 randomly selected companies that conduct research and development on new treatments for bacterial infections. We included companies that are researching or developing both traditional antibiotics and alternatives to antibiotics—which we call “nontraditional products” in this report—and we included companies that had and had not received funding from the Combating Antibiotic- Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) and companies that do and do not have existing FDA-approved drugs on the market. We asked company representatives about challenges in developing new antibiotics they have identified, support they may have received from federal agencies, how effective the support has been to them, and their views on additional incentives that would promote the development of new antibiotics. We also interviewed experts on the topic of antibiotic development and industry stakeholders, specifically The Pew Charitable Trusts and the Biotechnology Innovation Organization. We interviewed federal officials from BARDA, CMS, DOD, FDA, and NIH to learn about their programs and actions to support the development of treatments for antibiotic-resistant infections and requested information about funding for antibiotic R&D from BARDA, DOD, and NIH. We included relevant agency actions that began before the National Action Plan was issued in 2015 if they continued after 2015. Finally, we reviewed literature related to antibiotic development and reports about antibiotic pull incentives written by health policy advisory groups, including the PACCARB, the Transatlantic Taskforce on Antimicrobial Resistance (TATFAR), the DRIVE-AB project, and the Duke Margolis Center for Health Policy. We evaluated the actions taken by federal agencies to help address the challenges to developing new treatments against experts’ and advisory groups’ views on additional actions needed and against the principles related to developing strategies outlined in GPRA and the GPRA Modernization Act of 2010. We did not assess challenges to developing products designed to prevent infections, such as vaccines, nor federal actions related to these types of products. To examine federal agency efforts to promote the appropriate use of antibiotics and any challenges that remain, we also analyzed CMS data and related documentation on the quality measures and improvement activities related to antibiotics as part of CMS’s Merit-based Incentive Payment System (MIPS) in 2017. Specifically, we identified CMS’s antibiotics-related quality measures and improvement activities by conducting a search for the words “antibiotic,” “antimicrobial,” “bacteria,” “resistance,” and “resistant” on CMS’s MIPS website. We then reviewed CMS’s data on the number of MIPS-eligible clinicians who selected and reported on these measures and activities in 2017, the most recently available data. In 2017, there were nine MIPS quality measures related to antibiotics, as follows: (1) acute otitis externa: systemic antimicrobial therapy - avoidance of inappropriate use; (2) adult sinusitis: antibiotic prescribed for acute sinusitis (overuse); (3) adult sinusitis: appropriate choice of antibiotic: amoxicillin with or without Clavulanate prescribed for patients with acute bacterial sinusitis (appropriate use); (4) appropriate testing for children with pharyngitis; (5) appropriate treatment for children with upper respiratory infection; (6) appropriate treatment of Methicillin-sensitive Staphylococcus aureus bacteremia; (7) avoidance of antibiotic treatment in adults with acute bronchitis; (8) perioperative care: selection of prophylactic antibiotic – first- or second-generation Cephalosporin; and (9) total knee replacement: preoperative antibiotic infusion with proximal tourniquet. In addition, there was one MIPS improvement activity related to antibiotics in 2017: implementation of antibiotic stewardship program. We reviewed the MIPS data for any obvious outliers or anomalies, and we determined that these data were sufficiently reliable for reporting the number of clinicians who reported implementing these quality measures and improvement activities. In addition, we reviewed aggregated data from CDC on the total number of eligible U.S. hospitals voluntarily reporting their antibiotic use data to a CDC system (the NHSN’s Antimicrobial Use Option); we then calculated the percentage of eligible hospitals reporting such data as of January 1, 2020. We assessed the reliability of the aggregated data by reviewing them for any obvious errors or missing data totals and inquiring with CDC officials about their source and any known reliability issues. We determined that these data were sufficiently reliable for reporting hospital participation rates in the system. We also reviewed selected articles on antibiotic use and stewardship— compiled from a variety of sources, including CDC documents and experts we interviewed—published in literature. In addition, we interviewed experts on antibiotic use and stewardship, including representatives from PACCARB, Emory University’s School of Medicine, the University of Minnesota’s Center for Infectious Disease Research and Policy, The Joint Commission, the Society of Infectious Diseases Pharmacists, The Pew Charitable Trusts, and the Association for Professionals in Infection Control and Epidemiology. We evaluated federal efforts and challenges against relevant National Action Plan objectives and milestones and Executive Order No. 13676. We focused on antibiotic use in the United States, rather than global antibiotic use. We conducted this performance audit from February 2018 to March 2020 in accordance with generally accepted government auditing standards. Those standards require that we plan and perform the audit to obtain sufficient, appropriate evidence to provide a reasonable basis for our findings and conclusions based on our audit objectives. We believe that the evidence obtained provides a reasonable basis for our findings and conclusions based on our audit objectives. Appendix II: Expert Meeting Participant List We collaborated with the National Academy of Sciences to convene a two-day meeting of experts to inform our work on federal efforts to address antibiotic resistance; the meeting was held on September 17 and 18, 2018. The experts who participated in this meeting are listed below. Many of these experts gave us additional assistance throughout our work, including by providing additional technical expertise and answering questions, and 10 of these experts reviewed and provided comments on our draft report for technical accuracy. Appendix III: Additional Examples of Federal Efforts to Support Antibiotic Research and Development This appendix contains additional examples of efforts by agencies within the Departments of Health and Human Services, Defense, and Energy to provide support for antibiotic research and development beyond those mentioned in the report. These examples do not comprise the full extent of agencies’ efforts. Appendix IV: Additional Information on Federal Efforts to Promote Appropriate Antibiotic Use This appendix contains more detailed information on federal efforts to promote the appropriate use of antibiotics in health care through antibiotic stewardship programs and activities, organized by agency. These examples do not comprise the full extent of agencies’ efforts. Appendix V: Comments from the Department of Health and Human Services Appendix VI: GAO Contacts and Staff Acknowledgments Staff acknowledgments In addition to the contacts named above, John Neumann (Managing Director); Will Hadley, Anne K. Johnson, and Sushil K. Sharma, PhD, DrPH (Assistant Directors); Josey Ballenger, Hayden Huang, PhD, and Laura Tabellion (Analysts-in-Charge); and Amber Sinclair, PhD, made key contributions to this report. Nora Adkins, George Bogart, Jehan Chase, Anika McMillon, Laurie Pachter, Eric Peterson, Sarah Sheehan, Ben Shouse, Sara Sullivan, Walter Vance, Harris Weisz, and Emma Williams also made important contributions.