## EXECUTIVE SUMMARY

### III. Greater Coordination of Relevant Federal Agencies’ Efforts

• 1. The Strategies to Address Antimicrobial Resistance (STAAR) Act (H.R. 2400 in the 111th Congress) should be further strengthened, as outlined in this paper, and enacted to establish within HHS: a) an Antimicrobial Resistance Office (ARO); and b) a Public Health Antimicrobial Advisory Board (PHAAB) composed of non-government experts to support the work of the existing Interagency Task Force on Antimicrobial Resistance, and strengthen coordination, prioritization, and accountability of federal efforts.

### V. Strengthening Activities to Prevent and Control Antimicrobial Resistance

• 1. Current law should be strengthened to improve antimicrobial resistance prevention and control efforts through novel and innovative mechanisms.

• 2. Antimicrobial stewardship (i.e., coordinated interventions designed to improve appropriate use of antimicrobial drugs, including preventing inappropriate antimicrobial use and limiting antimicrobial exposure) is a critical tool to protect antibiotics from misuse and overuse. New incentives and requirements must be established for implementation and maintenance of successful antimicrobial stewardship programs across all health care settings (e.g., hospitals, long-term care facilities, long-term acute care facilities, ambulatory surgical centers, dialysis centers, outpatient clinics, private practices), including by requiring stewardship programs as a condition of participation in the federal Medicare and Medicaid programs or through another regulatory mechanism.

• 3. CDC's educational efforts on appropriate use of antimicrobials, including the Get Smart program, serve as a critical starting point for establishing antimicrobial stewardship programs. These educational efforts must be expanded for providers and patients.

• 4. Research is needed to define “inappropriate” antimicrobial prescribing and to better understand the primary drivers of such use.

• 5. Research is needed to define optimal components and goals of antimicrobial stewardship programs in different health care settings, including clinically relevant patient outcomes, and to develop national metrics to monitor program success.

• 6. An AIC Fee should be established, 25% of which should be used to fund antimicrobial stewardship program implementation and 75% of which should be used to fund new antibiotic development (see recommendation I.2).

• 7. Rapid molecular diagnostics are urgently needed to support appropriate antimicrobial use (see recommendation VII).

• 8. FDA should study and implement mechanisms to prevent over-prescription of antibiotics.

• a. As discussed in recommendation II.4, new clinical trial pathways should be established by regulatory guidance that enable companies to seek approval for organism-specific, narrow indications (e.g., infections caused by resistant GNB). Current FDA approval processes may be antithetical to antimicrobial stewardship principles. For example, antibiotics with broad activity, including against resistant GNB, have been licensed for the treatment of skin infections that are caused by a narrow spectrum of bacteria for which other effective options are available. By using new approval pathways focused on medical need, FDA can help limit the overuse of newly approved broad spectrum antibiotics (e.g., those that kill resistant GNB) by preventing their use to treat infections caused by a narrow spectrum of bacteria (e.g., skin infections not caused by GNB).

• b. Other strategies to protect antibiotics post-approval should be considered, such as a REMS-like program for antibiotics.

### VI. Significant Investments in Antimicrobial-Focused Research

• 1. The Antimicrobial Resistance Strategic Research Plan called for in the STAAR Act should be developed and implemented with a particular focus on antibiotic resistance.

• 2. Basic science research should be expanded to further study antimicrobial resistance mechanisms and epidemiology; identify new lead compounds; and develop vaccines, immunotherapies, and other technologies to prevent and treat infections in humans and animals.

• 3. Support for translation of promising compounds from pre-clinical research into clinical trials should be expanded.

• 4. Clinical and health outcomes research is needed to: a) define the natural history, outcomes, and magnitude of antimicrobial benefit for treatment of infections; and b) conduct comparative-effectiveness studies to define shorter durations of antimicrobial therapy and clinical and laboratory parameters that support early cessation of therapy.

• 5. Research is needed to optimize the PK/PD of antimicrobial therapy.

• 6. A clinical trial network is needed to support studies of antimicrobial therapies and antimicrobial resistance, building on the success of the existing HIV/AIDS clinical trials network.

• 7. Funding to support career development and faculty retention is necessary to reverse the “brain drain” that continues to occur in antibiotic and microbiology research in both academia and industry.

• 8. Annual funding for NIAID should be increased by $500 million by direct appropriation to support expansion of its antibiotic resistance and development research portfolio. ### VII. Greater Investment in Rapid Diagnostics R&D and Integration into Clinical Practice 1. Novel molecular diagnostics are needed that improve clinical care and public health. Such diagnostics can rapidly identify which illnesses are due to non-bacterial pathogens (e.g., viruses) and therefore do not need antibiotic therapy, which illnesses are due to bacteria and require antibiotic therapy, and which illnesses are due to drug-resistant bacteria. Ideally, these tests will be inexpensive, rapid, sensitive, specific, and able to be used close to or at point-of-care, and will lead to improved health care outcomes, reduced health care costs, reduced antibiotic resistance, and enhanced novel antibiotic development. 2. Federally-supported research and economic incentives are necessary to support R&D of novel molecular diagnostic tests and to strongly encourage their integration into clinical practice. 3. To limit the need for repetitive, expensive clinical trials and support rapid, efficient development and approval of new molecular diagnostic tests, a well-characterized clinical sample repository should be established by NIAID and FDA. ### VIII. Eliminating Non-Judicious Antibiotic Use in Animals, Plants, and Marine Environments 1. The Preservation of Antibiotics for Medical Treatment Act (PAMTA) (H.R. 1549/S. 619 in the 111th Congress) and/or other measures (including FDA regulations) should be adopted to end use of antibiotics for growth promotion, feed efficiency, and routine disease prevention purposes in animal agriculture and to ensure that these precious drugs are being used wisely in all settings. All use of antibiotics in animal agriculture should be carried out under the supervision of a veterinarian using a prescription or other practical mechanism, and over-the-counter purchases must be prohibited. 2. FDA Guidance #152 (“Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern”) should be revised to re-evaluate the current ranking of drugs according to their importance to human medicine. The guidance's scope should be broadened beyond enteric (food-borne) pathogens. 3. FDA must complete and publish safety reviews of those antibiotics of importance to human medicine that are approved for non-therapeutic purposes in food-producing animals, examining their role in the selection and dissemination of antibiotic-resistant food-borne pathogens. ### CONCLUSIONS The availability of effective antibiotics is not a “lifestyle” issue, and the lack of availability of these agents is not theoretical. Society worldwide is facing a public health crisis due to stagnation in the antibiotic drug pipeline combined with rapidly spreading, deadly antibiotic-resistant pathogens. The lack of effective antibiotics already is resulting in deaths and maiming of patients and the problem will only continue to worsen until Congress and the Administration act. The time for debate about the problem has passed. Immediate action is critically needed now. ## INTRODUCTION In 2000, Nobel Laureate Dr. Joshua Lederberg wrote in the journal Science that “the future of humanity and microbes will likely evolve as episodes…of our wits versus their genes” [13]. In only 11 years since Dr. Lederberg wrote these prescient words, the world has witnessed an enormous expansion of infections resistant to antibacterial agents (“antibiotics”). For example, methicillin-resistant Staphylococcus aureus (MRSA) infections, which were traditionally only noted among hospitalized patients, have become endemic in community settings [14–19]. Antibiotic-resistant Gram-negative bacteria (GNB) also have spread widely through US and global health care systems. Increasingly they have become resistant to all antibiotics available for treatment: i.e., pan-drug resistant (PDR). Examples of these PDR GNB organisms include Acinetobacter baumannii [20–29], carbapenemase-producing Klebsiella pneumoniae [30, 31], and Pseudomonas aeruginosa [28, 29, 32, 33]. Extended-spectrum beta lactamase (ESBL)-producing Enterobacteriaceae (e.g., Escherichia coli and Enterobacter spp.), often resistant to all orally administered antibiotics, have spread through health care systems and more recently into communities [34–44]. Most recently, a new antibiotic resistance mechanism (New Delhi metallo-β-lactamase 1 or NDM1) emerged in India and spread to communities in the United Kingdom [45] and the US [44]. NDM1 E. coli and Klebsiella strains are resistant to all antibiotics except tigecycline or colistin, and in some cases to these drugs as well [44, 45]. Collectively, highly problematic antibiotic-resistant organisms are summarized by the ESKAPE mnemonic: Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, and ESBL (Enterobacter and E. coli). ESKAPE indicates that these bacteria have developed defenses that permit them to escape the actions of available, effective therapies. The ESKAPE pathogens are currently the most important causes of the antibiotic resistance crisis in the US and other developed countries [11, 46]. Such pathogens also are spreading through developing countries, which already are experiencing significant public health problems from extreme drug-resistant (XDR) or PDR Mycobacterium tuberculosis (TB). Collectively, disease caused by the ESKAPE pathogens, TB, and other highly problematic antibiotic-resistant bacterial pathogens, including hypervirulent and fluoroquinolone-resistant Clostridium difficile, and multi-drug resistant (MDR) Streptococcus pneumoniae and Neisseria gonorrhoeae, result in enormous morbidity, mortality, and health care expense in the US and throughout the world [2, 3, 6, 9, 10, 47–49]. Just one organism, methicillin-resistant Staphylococcus aureus (MRSA), kills more Americans every year (∼19,000) than emphysema, HIV/AIDS, Parkinson's disease, and homicide combined [2]. Almost 2 million Americans per year develop hospital-acquired infections (HAIs), resulting in 99,000 deaths [3], the vast majority of which are due to antibiotic-resistant pathogens. Indeed, two common HAIs alone (sepsis and pneumonia) killed nearly 50,000 Americans and cost the US healthcare system more than$8 billion in 2006 [4]. In a recent survey, approximately half of patients in more than 1,000 intensive care units in 75 countries suffered from an infection, and infected patients had twice the risk of dying in the hospital as uninfected patients [5]. Based on studies of the costs of infections caused by antibiotic-resistant pathogens versus antibiotic-susceptible pathogens [6–8], the annual cost to the US health care system of antibiotic-resistant infections is $21 billion to$34 billion and more than 8 million additional hospital days. Antimicrobial resistance was recently recognized as one of the greatest threats to human health on the planet [1], so much so that the World Health Organization (WHO) has proclaimed antimicrobial resistance the focus of World Health Day (April 7) 2011.

The problem of antimicrobial resistance is not specific to bacteria—medically important viruses (e.g., HIV, influenza), fungi (e.g., Candida, Aspergillus), and parasites (e.g., malaria) also develop antimicrobial resistance. However, a unique convergence of overuse and misuse of antibiotics, the remarkable genetic plasticity of bacteria, the acquisition of resistant bacterial infections in both community and hospital settings, and a market failure of antibiotic development has created an enormous public health concern regarding antibiotic resistance in bacteria. For this reason, antibiotic resistance is the primary focus of this policy paper.

Paradoxically, concomitant with the rise of antibiotic-resistant bacteria, US Food and Drug Administration (FDA) approval of critically needed new antibiotics has dramatically slowed (Figure 1) [9–12]. Of great significance, nearly all major pharmaceutical companies have withdrawn from or greatly downsized their antibiotic research and development (R&D) programs over the past two decades, and the egress from the market is actively continuing. The combined threat of increasing numbers of drug-resistant bacteria and the diminishing antibiotic pipeline places us at risk not only from health care-associated and community-acquired infections, but from threats (bioterrorism, pandemics) that could affect our nation’s security.

To reverse this trajectory and call policymakers’ attention to the growing crisis, IDSA launched its Bad Bugs, No Drugs advocacy campaign in 2004 [49]. Unfortunately, antibiotic resistance and the waning approvals of new antibiotics have only worsened since 2004. Since then, IDSA has undertaken many clinical, scientific and public policy activities, including: 1) published practice guidelines on the development of antimicrobial stewardship programs for hospitals [50] and on the prevention and management of C. difficile infections [51], along with the Society for Healthcare Epidemiology of America; 2) co-sponsored, along with FDA's Center for Drug Evaluation and Research (CDER), workshops on the development of new antibiotics for Community-Acquired Bacterial Pneumonia (CABP) [52, 53] and Hospital-Acquired Bacterial Pneumonia/Ventilator-Associated Bacterial Pneumonia (HABP/VABP) [54]; 3) published data in support of new antibiotic development for skin and soft tissue infections [55]; 4) co-sponsored, along with FDA's Center for Devices and Radiological Health (CDRH), a workshop on diagnostics for respiratory infections; 5) proposed new research protocols on optimizing antibiotic effectiveness and antimicrobial stewardship for federal support; 6) testified at FDA Anti-Infective Drug Advisory Committee meetings and other FDA hearings and at Congressional briefings and hearings; 7) supported the Institute of Medicine Forum on Microbial Threats’ 2010 Workshop on Antimicrobial Resistance [56]; and 8) assisted members of Congress in drafting legislation introduced in the 110th and 111th sessions of Congress designed to directly address antimicrobial resistance issues [9].

In 2010, in recognition of the need for creative, new ideas to address the antibiotic pipeline problem and a measurable goal by which to gauge progress, IDSA launched the “10 × ’20 initiative” [57]. The 10 × ’20 initiative calls for the development of 10 novel, safe and effective, systemic antibiotics by 2020. Forty-five public health organizations and professional societies across the spectrum of medicine, including the American Medical Association and American Academy of Pediatrics, have endorsed the 10 × ’20 initiative [58]. Aside from the short term goal of increasing availability of critically needed new antibiotics, the underlying theme of 10 × ’20—akin to Dr. Lederberg's warning about the future of human-microbe relations—is the need to establish an infrastructure that recognizes and responds to ongoing changes in antibiotic resistance and facilitates antibiotic R&D in perpetuity.

In August 2010, the Administration, via the US Department of Health and Human Services (HHS), announced a broad plan as part of HHS's Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Review: Transforming the Enterprise to Meet Long-Range National Needs [59]. The plan focused on advancing the development of new countermeasures, including antibiotics, to address public health emergencies and national security threats. The Administration should be commended for this effort and its support, but antibiotics are in stiff competition for the limited resources necessary to support all aspects of the plan, and Congress has yet to advance new funding to support the initiative.

Members of the US Congress have begun to respond in other ways to the highly complex, interrelated public health and antibiotic research and pipeline problems. Although some legislation has been enacted over the past decade, more substantive legislation is needed. Recently, legislation has been introduced containing incentives to spur industry to develop new, priority antibiotics (and related diagnostics) and to press FDA to resolve multiple disincentives that are contributing to the market failure of antibiotic development (H.R. 6331, the Generating Antibiotic Incentives Now [GAIN] Act, introduced by Rep. Phil Gingrey [R GA-11], an obstetrician, in the 111th Congress). Other legislation has been introduced to strengthen the federal response to antimicrobial resistance, and antibiotic resistance in particular, through better coordination of efforts and enhanced surveillance, research, and prevention and control efforts (H.R. 2400, the Strategies to Address Antimicrobial Resistance [STAAR] Act, introduced by Rep. Jim Matheson [D UT-2] in the 111th Congress). Finally, legislation has been introduced to prevent non-judicious uses of antibiotics in animal agriculture (H.R. 1549/S. 619, the Preservation of Antibiotics for Medical Treatment Act [PAMTA], introduced by Rep. Louise Slaughter [D NY-28] and the late Sen. Edward Kennedy [D-MA] in the 111th Congress).

In July 2010, the Senate Appropriation Committee voiced its concern (see Appendix B) calling antibacterial resistance and the resulting failure of antimicrobial therapies in humans “a mounting public health concern,” and highlighting the “unresolved scientific issues regarding clinical development in the antibacterial drug arena, which has been identified as a serious impediment to new antibacterial development” [60]). The Senate Committee directed the National Institute of Allergy and Infectious Diseases (NIAID) of the National Institutes of Health (NIH), HHS’ Office of the Assistant Secretary for Preparedness and Response (ASPR), and ASPR's Biomedical Advanced Research and Development Authority (BARDA) to strengthen funding and make more seamless efforts to develop new antibiotics, particularly to treat problematic GNB, as well as much needed diagnostics. FDA was urged to issue clinical trial guidance documents that provide a clear approval pathway to drug companies. Further, FDA was asked to identify ways to promote the development and/or appropriate use of priority antibiotics for humans as current market incentives are inadequate. The agency was asked to report back to the Senate Committee on each of these requests by December 2010 [61]. As of March 2011, this has not yet occurred.

To continue momentum in this area, advance a broad public policy response, and accelerate significant new investment in research to address antibiotic resistance, on July 26–27, 2010, the IDSA, FDA, and NIAID co-sponsored a public workshop on “Antibacterial Resistance and Diagnostic Device and Drug Development Research for Bacterial Diseases.” The workshop's goals were:

“To discuss the scientific data addressing key issues in the following areas: the scale of the current bacterial resistance problem including extent, trajectory, and cost; the science and mechanisms of bacterial resistance; the science of development of rapid diagnostic devices; the science of antibacterial drug development.” (Videos, slides, and transcripts of the workshop are available on the IDSA website at http://www.idsociety.org/arworkshop.html.)

This policy paper summarizes IDSA's recommendations about how to address the discovery and development of new antibiotics, prevention of antibiotic resistance, and the development of rapid diagnostics that will enable more directed therapy. IDSA's goal is to represent the best interests of patients and health care professionals by recommending public policy strategies and research activities to address antibiotic resistance and save lives. These recommendations are derived from discussions and conferences (including the FDA/NIAID/IDSA July 2010 workshop) encompassing experts from academia, industry, and government in the fields of antimicrobial resistance, pathogen diagnosis, and drug development.

IDSA's eight broad areas of focus for its policy recommendations include the need to: 1) adopt economic incentives and support other collaborative mechanisms to address the antibiotic market failure by rekindling antibiotic R&D; 2) create new regulatory approaches to facilitate the clinical development of antimicrobials; 3) more effectively coordinate federal antimicrobial resistance efforts; 4) enhance antimicrobial resistance surveillance and data collection; 5) strengthen activities to prevent and control antimicrobial resistance; 6) strengthen investments in antimicrobial-focused research; 7) strengthen investment in development and utilization of rapid molecular diagnostics for infectious diseases; and 8) eliminate non-judicious antibiotic use in agriculture and other settings. Specific recommendations for Congress related to legislative action and funding needs are summarized in Tables 1 and 2, respectively.

## IDSA RECOMMENDS:

### I. Adoption of Economic Incentives and Support for Other Collaborative Mechanisms to Address the Market Failure of Antibiotics

#### 1. Statutorily-defined Push/Pull Incentives are Urgently Needed to Correct the Current Market Failure and to Motivate Companies to Reengage in Antibiotic (and Related Diagnostics) R&D.

Within pharmaceutical companies’ internal deliberations about how best to invest R&D resources, antibiotics are at a distinct disadvantage compared with most other drug categories. The return-on-investment potential (known as Net Present Value [NPV] in industry parlance) of antibiotics, which are normally taken for one to two weeks, cannot compete with drugs that treat chronic diseases, which are taken for months or years [9, 62–67]. A combination of factors has resulted in a market failure of new antibiotic development, including the ability of antibiotics to cure most infections in just a few days, antibiotic resistance which makes the drugs less effective over time, and deliberate and essential measures taken by physicians to limit antibiotics’ use to protect their effectiveness over time [9, 11, 48, 62, 67].

IDSA and others have extensively published on the need for statutorily-defined economic incentives to improve the return-on-investment/NPV calculation of antibiotics and make them more competitive with other therapeutic products as candidates for development [47–49, 57, 62]. To fix the broken antibiotic pipeline and create a sustainable R&D enterprise, it is necessary to determine the right combination of economic incentives (“push” and “pull” mechanisms) to entice companies to reengage in antibiotic R&D [9, 10, 48, 66]. Examples of push incentives are grants, contracts, and tax credits. Examples of the pull incentives are guaranteed markets, liability protection, patent extensions, data and market exclusivity, and prizes.

Such incentives are the focus of important bipartisan legislation, the GAIN Act (H.R. 6331 in the 111th Congress), which was first introduced in the US House of Representatives on September 29, 2010. The GAIN Act provides an excellent starting point for discussing the right combination of incentives needed to jumpstart novel antibiotic (and related diagnostic) R&D. As discussed in recommendation VII, the availability and clinical application of diagnostic tests are incredibly important to appropriately treat antibiotic-resistant infections and to support new antibiotic R&D. Recommendation VII.2 includes specific economic incentives targeting diagnostic development for Congressional leaders’ consideration. The GAIN Act's co-sponsors should be commended for their efforts to date. IDSA is working with them to strengthen the bill for its reintroduction and enactment in the 112th Congress. As deliberations move forward, Congressional leaders, including the GAIN Act co-sponsors, should discuss incentives with representatives of the European Commission, as the European Union has set a December 2011 deadline for evaluating and developing an action plan of concrete incentives to spur antibiotic R&D [68].

#### 2. New Public-private Partnerships Should be Established and Existing Government-Supported Collaborations Strengthened to Supplement (But Not Replace) Traditional Industry R&D for Critically Needed Antimicrobial Drugs.

To address infections caused by MDR/XDR/PDR bacteria, for which market challenges are extreme, new, non-profit public-private partnerships (PPPs) should be established and government-supported collaborative programs (ASPR's BARDA and proposed independent strategic investment firm, and NIAID-supported Cooperative Research and Development Agreements [CRADA]) should be further strengthened. The intent of such public-private collaborations is to advance the development of promising lead compounds toward approved products.

Since a PPP focused on antibiotic development would not be profit-driven, it could focus on developing critically needed drugs for indications in which current markets are very small (e.g., drugs to treat XDR/PDR Acinetobacter and Klebsiella). Removing profit motive from the equation also will help to limit the marketing of “priority” antibiotics to more serious and life-threatening indications. Focusing sponsor's marketing programs will enhance stewardship (see recommendation V.2) of these drugs and will prolong their effectiveness. Thus, the advantage of the PPP is that it could merge antibiotic conservation efforts with new antibiotic R&D efforts. Examples of successful PPPs that are already underway targeting tuberculosis drug development and resistance include the World Health Organization's Stop TB Partnership [69], the Global Alliance for TB Drug Development [70], and the recently announced Critical Path to TB Drug Regimens (CPTR) [71].

It is important to note that PPPs are not meant to replace the essential activities of private companies in drug discovery and development. Rather, PPPs are intended to complement efforts to reinvigorate market-driven, for-profit antibiotic development. Private companies’ R&D activities must still be strengthened through powerful economic incentives, and additional companies must be lured back into this field. We cannot rely on an unproven PPP model to fix the current situation.

PPPs primarily target larger companies for which risk and insufficient return on investment are the primary barriers to antibiotic R&D, not resource availability. Government-supported collaborative programs, on the other hand, provide direct funding to companies to assist them in bridging what has come to be known as the “valley of death,” i.e., the financial chasm between conducting phase I clinical drug trials and much more expensive phase II clinical trials. Such programs include BARDA, established by Congress in 2006 as part of the Pandemic and All-Hazards Preparedness Act, and the independent strategic investment firm announced in August 2010 as part of HHS’ PHEMCE review [59]. BARDA is intended to provide an integrated, systematic approach to the development and purchase of the necessary vaccines, drugs, therapies, and diagnostic tools for public health medical emergencies with the potential to impact national security. The strategic investment firm is intended to spur the development of new antimicrobial drugs and other high priority products by sharing the risk of development with companies and will help these companies leverage additional private investment in these important products.

In contrast to the PPP model, BARDA and the strategic investment firm likely will be most attractive to small and mid-sized companies, for which resource availability is a primary barrier to completion of clinical development. Congress’ support for BARDA's antibiotic efforts and for establishing and funding the strategic investment firm are essential. BARDA and the strategic investment firm will fund companies to “push” promising products from pre-clinical into clinical trials. BARDA then can use larger amounts of funding to “pull” critically needed products across the gap between phase I and phase II clinical trials.

The PPP and government agency support can be funded by both public monies and private capital. Government funding could be provided by the agency in the form of grants or contracts, including through matching funds, for example at a 2:1 ratio of private capital from the applicant company to government funding. With respect to public monies, IDSA proposes creation of an Antimicrobial Innovation and Conservation (AIC) Fee. The AIC Fee would be a flat fee (e.g., ∼$3 per daily dose, inflated by the consumer price index annually) charged against the wholesale purchase of every daily dose unit of antibiotics (both branded and generic) in the US, including for human, animal and plant agriculture, and aquaculture use. The fee would be paid by the dispensing entity (e.g., pharmacy, animal feed mill, aquaculture company, etc.) at the time of wholesale purchase from the supplier. The rationale for such a fee is that effective antibiotics represent a “shared societal benefit,” and every antibiotic manufacturer, prescriber, and user must share the responsibility to maintain this benefit. Antibiotic resistance resulting from antibiotic use (both appropriate and inappropriate) is an example of the “tragedy of the commons” [72]. A prescription may help the individual patient, plant, or animal, but such use also causes collective erosion of the benefit (effectiveness of antibiotics) for society as a whole. Analogously, use of highways by a vehicle has a cost to all users. Tolls (and differential rates) are means to have users pay their fair share of societal costs for establishing and maintaining a shared benefit. Because of the emergence of resistance, use of antibiotics differs from use of all other drugs that affect only the individual patients taking them. Hence, an AIC Fee would be charged to maintain the “shared societal benefit” of effective antibiotic therapy. Obviously, safeguards need to be incorporated into the AIC Fee structure to ensure that any costs passed on to consumers will not negatively impact vulnerable populations’ access to these important drugs. As described in recommendation V.6, 25% of the AIC Fee would be allocated to a CDC antimicrobial stewardship fund. The remaining 75% of the AIC Fee could be allocated to a trust fund established under the management of ASPR within HHS, to support the development of promising, high priority candidate antibiotics. This can occur through BARDA, the strategic investment firm, and a PPP. Other sources of public funding include appropriations and transfer of other federal agency funds. Government agency funds would be augmented by allocation of matching private capital from application companies. The PPP would raise private capital through user fees, license payments, royalty sharing, and/or other methods. The PPP could develop its own drugs internally, and also would partner with industry to develop drugs. Industry would use the PPP to develop promising molecules with very limited market potential, such as a drug that could only target bacteria causing relatively small numbers of infections per year, or for drugs with high risk but high potential payoff if development was successful. In such cases, industry would license the drug to the PPP, which then would take charge of developing the molecule from pre-clinical through phase II trials, with a plan to partner back with the licensing company to co-develop for phase III trials, if the drug made it that far. If the drug was successful in phase III trials, the partnering company would manufacture, distribute, and market the drug and would share royalties with the PPP based on pre-agreed terms. If after completion of phase II trials, the originating company decided not to participate in phase III trials, the PPP would be free to seek alternate private partners to complete clinical development, manufacturing, marketing, and distribution of the drug. The PPP also could raise private money in other ways. Federal funding agencies, such as BARDA, and the proposed federal strategic investment firm must have the capacity and dedicated funding to create financial grants, contracts, venture capital investments, and partnerships with industry to stimulate the discovery and development of antibiotic and related diagnostics. In addition to supporting an annual commitment of$500 million at NIAID to strengthen the agency's antibiotic resistance and antibiotic discovery research portfolios (see recommendation VI.8), IDSA calls for: 1) an annual allocation of at least $1.7 billion of multi-year funding to BARDA to facilitate development of therapeutics, diagnostics, vaccines, and other technologies, including new antibiotics and diagnostics to treat and detect infections caused by ESKAPE and other serious and life-threatening pathogens; and 2) at least$200 million to support the new strategic investment firm's antibiotic venture capital investments.

Such funding would facilitate creation of entire drug and diagnostics portfolios within sponsors, evolving away from funding a single program that is high risk for the funder and provides poor flexibility for the company.

#### 3. Value-based Reimbursement Strategies that Encourage Antibiotics and Related Diagnostics Development Must be Pursued.

Adopting reimbursement rates that are more aligned with antibiotics’ and related diagnostics’ true value is another critical way to stimulate new antibiotic and rapid diagnostics development. Antibiotics, in particular, often are undervalued when one considers the benefits they bring in terms of numbers of lives saved, increased disability-adjusted life years (DALYs), increased productivity, and reduced health care costs [66, 73, 74]. Policymakers should rethink current reimbursement strategies to reward sponsors of innovative products, particularly those products that address areas of unmet medical need. Specific criteria to consider in appropriately valuing an antibiotic is whether the drug possesses a broader spectrum of antibacterial activity or a better safety profile than existing drugs, or whether it treats highly drug-resistant pathogens or employs a new mechanism of action. Also to consider are whether the drug was approved based on superiority trials and the drugs’ potential for reducing health care expenditures (e.g., lengths of hospital stays, etc.).

Finally, novel reimbursement strategies must be considered that strongly reward antibiotic drug pioneers who agree to forgo broad (and more profitable) FDA-approved label indications for indications that narrowly target high priority public health needs (see related recommendation V.8). Such strategies could help to avoid rapid depletion of a priority antibiotic's effectiveness by limiting its overall marketing potential.

#### 4. A Panel of Experts Should be Established to Document and Regularly Revise a List of Priority Pathogens or Infections Against Which Incentives Should be Targeted.

A panel of experts, envisioned as a qualifying antimicrobial product committee (QAPC), comprised of representatives from government agencies such as FDA, CDC, NIAID, BARDA and ASPR, as well as academic or private infectious diseases specialists and public health experts, should be established under the GAIN Act or similar legislation to document and regularly revise a list of those priority pathogens or infections that have created or likely will create an area of unmet medical need and toward which adopted economic incentives should be targeted. The QAPC perhaps could be established as a subgroup of the STAAR Act's advisory board (see recommendation III) to streamline efforts.

### II. New Regulatory Approaches to Facilitate Antimicrobial Development and Approval

#### 1. Clear and Feasible Regulatory Guidelines on Clinical Trial Designs are Urgently Needed to Enable Approvals of New Antibiotics and Other Antimicrobials.

Clinical development of promising antimicrobial agents cannot proceed in the absence of clarity regarding the requirements for licensure of the drugs. Considering together the economic disincentives antibiotic developers currently are facing (see recommendation I) and the lack of a clear regulatory approval pathway for these drugs over the past decade, one can easily understand why antibiotic approvals have decreased so markedly and companies have withdrawn from antibiotic R&D to pursue more lucrative areas of drug development. To correct this imbalance, FDA must quickly assure clear and feasible regulatory pathways for the development of antibiotics by issuing clinical trial guidance documents for industry that contain designs the agency will find acceptable. Such guidelines should recognize the importance of making pivotal studies clinically relevant, and should strike a balance between clinical reality and statistical desirability. Guidance is needed both for non-inferiority and superiority studies (see Appendix C for an overview on both types of trials); currently no clear and feasible path exists for conduct of superiority trials. In setting regulatory guidance for antibiotic development, FDA must balance the public health risks of approving a potentially less effective drug with the risk of having no new, critically needed antibiotics available to treat patients infected with resistant pathogens.

#### 2. Already Conservative Estimates of Antimicrobial Efficacy Relative to Placebo/no Therapy Should Not be Further “Discounted” When Setting Requirements for Non-inferiority Margins for Clinical Trials, as Discounting Results in Excessively Large Trial Requirements.

FDA should cease the practice of “discounting” already conservative estimates of antibiotic efficacy when setting requirements for non-inferiority margins, and hence trial size (i.e., the number of patients who have to be studied) for pivotal trials [55, 75]. The purpose of discounting is to account for limitations in the quality of historical data used to provide an estimate of how effective antibiotic therapy is versus placebo or no therapy. However, when the estimate of antibiotic effect size is already highly conservative, discounting results in an overly conservative, arbitrary mathematical calculation of non-inferiority margins [62, 75]. There is no logical basis for selecting how much of antibiotic efficacy to first “discount” and second “preserve” when setting non-inferiority margins. As a result, discounting results in arbitrary, subjective, and unjustified requirements to conduct very large clinical trials which are not feasible to execute. Such requirements have greatly contributed to the lack of new antibiotic R&D and the egress of industry from the antibiotic market [9, 12, 55, 62–64, 75, 76].

#### 3. The Primary Issue in Justifying the Non-inferiority Margin for a Clinical Trial is Determining How Much of the Clinical Benefit of Antimicrobial Therapy Must be Preserved, Which Should be Based Upon an Assessment of the Relative Merits of the Specific Experimental Drug Versus Currently Available Therapy.

The issue of how much of antimicrobial efficacy to “preserve” when setting non-inferiority margins is not a statistical question, it is a clinical question. Qualified experts in clinical medicine, who care for patients and know the current challenges and needs for improving treatment, possess the expertise required to define how much of a potential decrease in treatment benefit can be justified as a trade-off against the critical need to develop new efficacious and safe drugs and have them available for clinical use.

The treatment effect of antibiotic therapy for serious and life-threatening infections is very large (Table 3). Thus, for clinical trials of new antibiotics, the primary issue in justifying the non-inferiority margin is determining how much of that clinical benefit must be preserved. This decision should be justified based upon an assessment of the relative merits of the specific experimental drug. Regulators and physicians, as experts in public health needs, should be willing to accept a small increase in statistical imprecision regarding treatment effect size in return for facilitating development of critically needed new drugs, particularly if the experimental drug offers other substantive advantages over existing therapy. Factors to be considered include relative advantages of the experimental drug versus existing agents in antibiotic spectrum of activity (particularly activity against XDR and PDR pathogens), safety, or dosing, or the advantage of a novel mechanism of action. Wider non-inferiority margins should be tolerated for drugs with substantive advantages in these areas, whereas narrower margins should be required for drugs with little to no advantages in these areas.

Table 3.

Antibiotic-Mediated Mortality Reductions for Specific Infections

 Disease Pre-Antibiotic Mortality Rate Antibiotic Mortality Rate Change in Mortality Community Pneumonia [53] ∼ 23% ∼ 7% −16% Nosocomial Pneumonia [54] ∼ 60% ∼ 30% −30% Bacterial Endocarditis [112–115] ∼ 100% ∼ 25% −75% Bacterial Meningitis [116–117] >80% <20% −60% Skin Infection [55, 118] ∼ 11% <.5% −10% By comparison, treatment of myocardial infarction (i.e., heart attack) with aspirin or streptokinase [119] −3%
 Disease Pre-Antibiotic Mortality Rate Antibiotic Mortality Rate Change in Mortality Community Pneumonia [53] ∼ 23% ∼ 7% −16% Nosocomial Pneumonia [54] ∼ 60% ∼ 30% −30% Bacterial Endocarditis [112–115] ∼ 100% ∼ 25% −75% Bacterial Meningitis [116–117] >80% <20% −60% Skin Infection [55, 118] ∼ 11% <.5% −10% By comparison, treatment of myocardial infarction (i.e., heart attack) with aspirin or streptokinase [119] −3%

In short, as new antibiotics are critically needed, we must balance feasibility of conducting studies (and the resultant public health benefit of facilitating approval of effective new antibiotics) against a desire to narrow the non-inferiority margin. While patients may be harmed if less effective drugs are allowed to reach the market, they also may be harmed if they have an infection for which no effective antibiotics have been developed. Furthermore, if the criteria for study conduct are so strict that it is infeasible to enroll meaningful numbers of patients in the US, or the trial results are not generalizable post-approval, we run the risk that the observed safety and efficacy of the drug in its pivotal studies will not be informative regarding the safety and efficacy of the drug for patients in the US who are exposed to the drug. The key is to create a regulatory path that balances these competing risks.

#### 4. Regulatory Guidance is Needed to Create New Pathways to Facilitate Approval of Antibiotics.

Development of drugs for the treatment of infections caused by specific, problematic pathogens (e.g., ESKAPE pathogens) is stymied by: 1) lack of guidance on such development programs; 2) small market sizes, which provide insufficient financial incentive for companies to move into this area; and 3) the difficulty of identifying and enrolling patients with such infections.

Organism-specific studies, in which patients with multiple disease types are enrolled in a single study, similar to the path taken for studies of invasive fungal infections, can help mitigate these concerns. For example, the enrollment of patients with infections caused by resistant GNB causing a variety of serious or life-threatening infections, rather than a single type of infection, would greatly expand the target population for enrollment, making it more feasible to enroll the required number of subjects in studies. Furthermore, the market size of the resulting indication would be larger since multiple diseases would be studied from one trial, increasing the financial return on incentive for companies. Yet, all of the infections would be caused by antibiotic-resistant GNB, so marketing of the drug would be concordant with public health need, and the drug would not be wasted for treating less resistant organisms. For these reasons, regulatory guidance should be made available on conduct of organism-specific studies.

Regulatory guidance also is needed for other novel antibiotic studies, including acceptable design of superiority clinical trials and/or the use of historically controlled clinical trials. Finally, regulatory guidance is needed that permits FDA approval based on a relatively small clinical sample size (<100 patients) for infections caused by XDR/PDR GNB that occur in critically ill patients as well as to address future, potential areas of urgent unmet medical need.

Members of Congress (including the GAIN Act co-sponsors) should discuss with FDA officials whether expansion of the agency's existing statutory authority is needed to allow for conditional approvals and powerful post-approval approaches (e.g., Risk Evaluation Management Strategies [REMS]-like safeguards) for novel antibiotics that address urgent unmet medical needs (e.g., highly antibiotic-resistant XDR/PDR GNB). Alternatively, other statutory changes should be identified that agency officials agree would speed the development and approval of high priority, novel antibiotics. The GAIN Act already contains several promising ideas (e.g., fast-track approval, priority review, deadlines placed on clinical trial guidance development), but additional discussion with FDA is warranted specific to areas of urgent unmet medical needs.

#### 5. Regulatory Science Must Continue to be Advanced and Developed to Make Clinical Trial Designs Feasible, Clinically Relevant, and Scientifically Rigorous.

IDSA strongly supports the collaborative regulatory science effort recently initiated by FDA, NIAID, and the Foundation of the NIH (FNIH) along with industry, academia, and IDSA to examine surrogate endpoints for antibiotic clinical trials, as well as pharmacokinetic/pharmacodynamic (PK/PD) parameters that forecast optimal antibiotic dosing. Such antibiotic-focused R&D activities should be encouraged and further expanded. The Reagan-Udall Foundation, a public-private partnership established in 2007 between FDA and industry, provides another avenue for potential support. However, moving these critical activities forward will require dedicated funding from the federal government, industry, and other funding organizations.

To reiterate, FDA must balance the risk of approving a potentially less effective drug with the benefit of making a potentially life-saving therapy available sooner for patients who desperately need it. Therefore, FDA should consider alternatives or surrogates to traditional clinical trial endpoints (for example, other than survival) that are acceptable for regulatory approval as evidence of clinical benefit to patients. The use of novel statistical approaches, such as Bayesian methods, as a means to increase efficiency of clinical trials of antibiotic therapy should be encouraged. FDA should consider the pre-test probability of a drug's efficacy based on the totality of pre-clinical and phase I and II clinical trial data when setting parameters for planned pivotal phase III clinical trials, and when interpreting results of those trials.

### IV. Enhancement of Antimicrobial Resistance Surveillance Systems

#### 1. National Data on Antimicrobial Resistance Rates, Linked to Clinical Outcomes, Should be Gathered in Real Time and Made Publicly Available on a Regular Basis.

Currently, antimicrobial resistance rates are made public only sporadically. The STAAR Act includes provisions for strengthening surveillance on a national level for antimicrobial resistance and antimicrobial use. The systematic collection of data on antimicrobial, and particularly antibiotic, resistance is necessary for a variety of infections and pathogens. Specific data on type and quantity of antimicrobials used throughout the spectrum of patient care are needed to define the overuse and misuse of antimicrobial agents; only by understanding the scope and severity of the problem can interventions be developed to reverse the problem.

The European Union (EU) has successfully implemented systems across all 27 member countries to track antimicrobial resistance trends for public health purposes and to collect antimicrobial use data. The European Antimicrobial Resistance Surveillance Network (EARS-Net) [77] and the European Surveillance Antimicrobial Consumption (ESAC) [78], respectively, are funded by the European Centre for Disease Prevention and Control (ECDC). No system comparable to EARS-Net and ESAC exists in the United States. Just as in Europe, the capacity to analyze and disseminate such resistance trends and antibiotic use data must become a cornerstone of the US health care system.

IDSA recommends that national antimicrobial resistance rates be published annually or biannually. Furthermore, akin to the comprehensive CMS databases on health economics that are posted online to facilitate health economics research, the full linked database of susceptibility profiles, molecular epidemiology, and clinical outcomes should be available via the internet for research and public policy purposes.

#### 2. A Federally Funded Network of Sentinel Sites That Collects Both Clinical Specimens and Clinical Data is Necessary to Detect and Evaluate Rapidly Emerging Resistance in a Variety of Organisms and to Develop, Implement, and Evaluate Prevention Strategies.

To respond to current resistance trends, and to plan for emerging trends, it is necessary to understand the frequency of resistance to antimicrobial agents, and particularly antibiotics, among medically important pathogens across geographical areas. Data must be current to ensure correct intervention decisions. In addition, specimen collection is needed for the evaluation of emerging resistance mechanisms in pathogens of clinical importance. In short, an integrated network of sentinel sites with diverse geographic representation is required.

The STAAR Act requires the CDC and NIAID to establish and maintain a network of specialized sites: the Antimicrobial Resistance Surveillance and Research Network (ARSRN), to ensure ongoing accurate data and pathogen collection as well as to conduct relevant research (see recommendation VI). ARSRN sites would track cultures obtained from both inpatients and outpatients, assess resistance patterns, and report in real-time to a central antimicrobial resistance data management center. The ARSRN, and its component sites, also would conduct studies to assess resistance risks, develop interventions specific to those documented risks, and implement strategies, in collaboration with the CDC and NIAID, designed to mitigate the impact of resistant pathogens.

Current national surveillance systems lack the flexibility to rapidly establish surveillance for newly emerging resistant pathogens, collect specimens, identify the mechanisms of resistance in each pathogen, and identify the risk factors associated with acquisition of the pathogen by patients. While current national data collection efforts provide useful data on a variety of HAIs and on resistance rates of selected invasive pathogens, the US does not rapidly monitor and assess newly emerging resistance trends for many pathogens of medical importance.

For example, the existing National Healthcare Safety Network (NHSN) is a CDC-managed internet-based surveillance system that has defined modules of data collection in which health care facilities participate. Currently, more than 3000 facilities from all 50 states submit data to NHSN. Recently, CMS proposed a national requirement for submission of HAIs data to NHSN. However, NHSN does not encompass collection of microbial isolates, and the types of infection under surveillance are limited to those pre-specified by the data collection module.

Active Bacterial Core surveillance (ABCs) of the CDC Emerging Infections Program is an important population-based surveillance system that includes pathogen collection and can assess risk factors for infection and population-based impact of interventions, such as vaccines. However, ABCs is defined for selected pathogens from infections encompassing sterile body sites. As it is currently operating, ABCs cannot easily be modified to assess for the ongoing emergence of resistance among a changing variety of medically important pathogens, particularly infections involving non-sterile clinical sites (e.g., GI tract) where emerging resistance is frequently first evident.

In short, national surveillance efforts need to be strengthened and modified to encompass the rapid detection of emerging resistant infections. The development of the ARSRN will build upon the existing surveillance systems and provide an early warning system for evolving resistance in medically important pathogens, and a platform to rapidly assess control strategies that includes developing, implementing, and evaluating novel interventions that prevent the spread of resistant pathogens. The ARSRN will greatly enhance and dovetail with the overall national surveillance capacity.

IDSA is calling for a $500 million annual increase in Congressional appropriations to support an expansion of NIAID's budget in the area of antibiotic resistance and antibiotic discovery research. As discussed previously [46], NIAID is aware of the need for additional research to address the antimicrobial, and particularly antibiotic, resistance problem. However, the overall flat budget of NIH and NIAID limits the Institute's ability to sufficiently increase funding for critically needed new research in antibiotic resistance and development, [103] as elaborated above. ### VII. Greater Investment in Rapid Diagnostics R&D and Integration into Clinical Practice #### 1. Novel Molecular Diagnostics are Needed that Improve Clinical Care and Public Health. In a policy paper on molecular diagnostics for respiratory tract infections, IDSA called for the development and clinical use of novel, molecular diagnostic tests to improve rapidity, sensitivity, and specificity of making a microbial diagnosis of infection [104]. These efforts need to be expanded to cover the full spectrum of sites of human infection and the potentially different approaches needed based on the patient's condition (e.g., solid-organ or bone marrow transplant, HIV-infected, cancer chemotherapy, and premature neonates). There are multiple benefits of such tests, as discussed below. Tests ideally should be: inexpensive, rapid, close to or at point-of-care, sensitive, and specific. Furthermore, use of such tests should ideally improve health care outcomes, reduce overall health care costs, serve a population benefit (e.g., reduce antibiotic resistance) by supporting antimicrobial stewardship efforts, and/or support novel antibiotic development by facilitating patient enrollment in pivotal clinical trials. #### 2. Federally-supported Research and Economic Incentives are Necessary to Support R&D of Novel Molecular Diagnostic Tests and to Strongly Encourage Their Integration Into Clinical Practice. To optimize use of novel molecular diagnostic tests, it is important that the tests be capable of detecting pathogenic bacteria, in addition to viruses. Diagnostic test panels must be established to support capability of the tests to identify bacterial pathogens. Tests ideally should detect pathogenic organisms from patient samples, in addition to pure cultures. The devices should facilitate detection of small numbers of organisms, rather than the larger number available in pure culture. Quantitative standards are needed to assist in the distinction between colonizing organisms and invasive pathogens, particularly in respiratory specimens. Tests should be validated in large numbers of samples to determine appropriate quantitative thresholds. As discussed in further detail in IDSA’s policy paper on rapid diagnostic tests for respiratory tract infections, clinical validation should not include use of the test to determine whether disease is present, only whether or not a specified organism is present in the sample [104]. Clinicians and clinical investigators should determine whether disease is present by integrating the results of diagnostic tests with all other clinical information. IDSA strongly supports the use of novel molecular diagnostic tests to enrich the microbiologically confirmed, evaluable population in antibiotic pivotal studies. This issue is discussed at length in the IDSA policy paper on molecular diagnostics [104]. Studies of molecular diagnostic tests should focus on their ability to facilitate prevention of antibiotic prescription for diseases that may be viral or non-infectious in etiology, to target initial antibiotic therapy to the appropriate bacterial pathogen in hospitalized patients, and to de-escalate or stop antibiotic therapy in patients in whom it has been empirically initiated. As Congressional leaders consider potential incentives to stimulate antibiotic development and ensure the appropriate use of these precious drugs, it is essential that incentives supporting the development and utilization of new, related diagnostic tests also be adopted. Such incentives may include: 1) defining improvements to the process for determining payment rates for qualifying diagnostic tests and developing a system for assigning temporary Healthcare Common Procedure Coding System (HCPCS) codes to new tests until a permanent code is established; 2) encouraging the development of companion diagnostics by extending the period of data exclusivity for an antibiotic for which the manufacturer has developed a companion diagnostic test, and/or creating a market exclusivity period for qualifying medical devices, if the manufacturer of such device co-develops a companion diagnostic test with an antibiotic; 3) requiring FDA to provide expedited review for qualifying devices; and 4) reimbursing relevant diagnostics appropriately based on their value to society (see recommendation I.3) #### 3. A Well-characterized Clinical Sample Repository Should be Established by Federal Agencies to Speed Validation of Molecular Diagnostic Tests. In principle, the simplest clinical validation study for a molecular diagnostic test would be comparison of the test to the “truth standard,” using prospectively characterized clinical specimens stored in a repository. The ability to access samples without conducting new and parallel clinical trials to obtain specimens would make validation much less expensive and faster. Such well-characterized clinical samples could be obtained, for example, from phase II or III clinical trials of drugs or devices. The samples should be collected in a prospective manner with a protocol defining inclusion and exclusion criteria, and linked to all clinical data available from the source patient, in addition to results of reference diagnostic tests. Sponsors would likely have to do bridging studies to show that fresh samples and frozen samples performed similarly with their assay. A repository would represent a significant advance over current sample collection performed by a pharmaceutical company for drug or device approval, in which each company exclusively owns all samples collected, and no cross-validation of samples for different agents all treating or diagnosing one clinical indication (e.g., pneumonia) is possible. One reasonable option would be to increase NIAID funding to support establishment of such a clinical specimen repository at FDA's CDRH, similar to the clinical cancer specimen repository that the National Cancer Institute supports. Furthermore, establishment of the ARSRN as part of the STAAR Act would enable collection of specimens outside of clinical trials in collaboration with highly proficient clinical microbiology laboratories. ### VIII. Eliminating Non-Judicious Antibiotic Use in Animals, Plants, and Marine Environments #### 1. PAMTA (H.R. 1549/S. 619 in the 111th Congress) Should be Enacted and Other Measures Adopted to End the Use of Antibiotics for Growth Promotion, Feed Efficiency, and Routine Disease Prevention Purposes in Animal Agriculture and to Ensure That These Precious Drugs are Being Used Wisely in All Settings. IDSA strongly supports enactment of PAMTA and the adoption of comparable measures (including FDA Center for Veterinary Medicine [CVM] regulations) to stop the use of antibiotics for growth promotion, feed efficiency, and routine disease prevention purposes in animal agriculture. IDSA also supports requiring prescriptions and veterinary oversight of all antibiotics given to animals. Antibiotic use in agriculture, similar to human medicine, should be carried out under the supervision of a veterinarian, within the boundaries of a valid veterinarian-client-patient relationship. In addition, FDA/CVM should: 1) define procedures for antibiotic administration in animals that will permit short-term antibiotic use for those animals that have a current therapeutic need or an immediate prophylactic need due to an infectious outbreak in surrounding animals where such animal has been exposed or is highly at risk for exposure to disease; and 2) work with CDC and USDA to expand post-approval surveillance under NARMS (see recommendation IV.2). As discussed in recommendation IV.3, the amount and type of antibiotics used in animal feed should be tracked and made publicly available on an annual basis. In addition, ongoing risk analysis is needed to better understand the impact of the remaining uses of antibiotics in animal agriculture on human and animal health (see recommendation VIII.3). #### 2. FDA/CVM Guidance #152 (“Evaluating the Safety of Antimicrobial New Animal Drugs with Regard to Their Microbiological Effects on Bacteria of Human Health Concern”) Should be Revised to Re-evaluate the Current Ranking of Drugs According to Their Importance to Human Medicine. IDSA urges a reassessment of existing FDA/CVM Guidance #152 [105], which is the framework by which the agency approves new antibiotic products for use in animals. FDA must reevaluate the current ranking of drugs according to their importance to human medicine. In particular, the agency should reconsider the criteria used to categorize antibiotics as “critically important” and “highly important” to human health. The scope of Guidance #152 criteria should be broadened beyond enteric pathogens. The current focus on enteric-only pathogens fails to consider the human health risk posed by horizontal gene transfer or clonal spread of resistant strains of bacteria, including such species as Enterococcus and E. coli, which are a normal part of the bacteria living in intestines of food animals, but cause infections outside the intestines in humans. #### 3. FDA Must Complete and Publish Risk Assessments of Those Antibiotics of Importance to Human Medicine that are Approved for Non-therapeutic Purposes in Food-producing Animals, Examining Their Role in the Selection and Dissemination of Antibiotic-resistant Food-borne Pathogens. FDA must complete, update, and publish risk assessments for antibiotics of importance to human medicine, which currently are approved for non-therapeutic purposes in food-producing animals. These reviews are necessary to ascertain the role of such use of antibiotics in the selection and dissemination of antibiotic-resistant food-borne pathogens. Since 2003, FDA/CVM has required that the pre-approval safety reviews for all new antibiotic veterinary drugs include an evaluation of the likelihood that the proposed drug use in animals will lead to resistant infections in humans. Because almost all antibiotics being used for growth promotion and other non-therapeutic purposes in livestock production were approved by FDA before 2003, most have either not undergone reviews with respect to antibiotic resistance or have undergone reviews that are inconsistent with current standards. To ensure that these drugs meet current safety standards, it is important that post-market safety reviews be done for those classes of antibiotics important to human medicine that also are being used for routine non-therapeutic purposes in animal agriculture. These would include penicillins, tetracyclines, macrolides, lincosamides, streptogramins, aminoglycosides, and sulfonamides. Such reviews are expensive:$5 million should be appropriated immediately to enable FDA to carry out this important work.

Antibiotics are commonly used outside of humans and animals in aquaculture, horticulture, and even in marine paint to limit barnacle growth. Antibiotic use in aquaculture is essentially unregulated and may result in significant environmental contamination, although data are lacking and additional research is needed. The use of antibiotics such as tetracycline, streptomycin, and gentamicin (which are used on plants and fruit to prevent fire blight), may be justified in limited circumstances, but monitoring of use and the development of resistance in target bacterial pathogens should be established. It is reasonable and prudent to minimize or prohibit the non-human use of any antimicrobial that has current or potential application for the treatment of infections in humans.

## CONCLUSIONS

It is difficult to accurately convey the enormous impact effective antibiotics have had in saving patients’ lives and eliminating tremendous suffering in the US and throughout the world. The most fundamental impact of the introduction of antibiotics was a dramatic decline in death from bacterial infections of all types. For example, the overall mortality rate from infectious diseases in the US fell by ∼220 per 100,000 population (75%) over the first 15 years of the antibiotic era [106]. Almost overnight, mortality rates for diseases such as pneumonia, endocarditis, and meningitis dropped substantially after the introduction of new antibiotics (Table 3). Indeed, so enormous were the mortality benefits of antibiotics that all subsequent medical advances since the early 1950s—including the advent of critical care medicine—have resulted in only minor further reductions in death from infections. Specifically, during the second half of the 20th century, despite all intervening advances in medical care, mortality rates from infections declined only by an additional 20 per 100,000, less than 10% of the decline achieved immediately following the availability of antibiotics [106]. The US federal government recognized this plateau effect in reduction of mortality from infections through the 1950s and 1960s, and understood [107] that it was due to the remarkable power of antibiotics [108–109].

Beyond saving lives of infected patients, today the enormous efficacy of antibiotics enables conduct of complicated and deeply invasive surgery, aggressive chemotherapy for treatment of cancer, fundamental elements of critical care such as central venous catheter placement and mechanical ventilation, supportive care for premature infants, and solid and liquid organ transplantation. None of these medical advances would be feasible without effective antibiotics to prevent and treat the infections that occur as a side effect of the advances themselves. Indeed, one of the leading physicians of the 20th century, Dr. Walsh McDermott, a Lasker Award winner who served as first president of the Medical Board of the National Academy of Sciences (precursor to the Institute of Medicine), commented that:

“It is not too much to state that the introduction of [antibiotics] has represented a force for change in the 20th century of the same general kind as James Watt's modification of the steam engine did in the 18th.” [110]

In short, as described by both Dr. McDermott and Dr. Lewis Thomas [111], the power of antibiotic therapy resulted in nothing less than a total revolution in the practice of medicine. Antibiotics fundamentally transformed the profession from a diagnostic, non-interventional field to a therapeutic, interventional profession.

The loss of effective antibiotic therapy due to antimicrobial resistance and the withering antibiotic R&D pipeline will result in a great increase in deaths from infections. This issue—the availability of effective antibiotics—is not a “lifestyle” issue, and the loss of such agents is not theoretical. We are facing a worldwide health crisis that already is resulting in deaths and maiming of patients, and will increasingly do so in the coming decades unless urgent action is taken. The time for debating the problem has passed. Immediate action is critically needed, as outlined in this policy paper.

This supplement is sponsored by IDSA and is dedicated to John G. Bartlett, MD, FIDSA for his tireless commitment to the work of the Society and toward combating antimicrobial resistance.

This policy paper stems from the critical, ongoing efforts of member experts who serve on IDSA's Antimicrobial Resistance Work Group, Research on Resistance Work Group, and Antimicrobial Availability Task Force. The paper's research recommendations stem, in particular, from discussions with and presentations by the planners and participants of a public workshop that occurred July 26-July 27, 2010, which was co-sponsored by FDA, NIAID and IDSA. The workshop's executive committee included Drs. Edward Cox (FDA's co-chair), Michael Kurilla (NIAID co-chair), Martin Blaser (IDSA's co-chair), Dennis Dixon (NIAID), David Gilbert (IDSA), and Louis Rice (IDSA). The workshop program committee also included: 1) for IDSA, Drs. John G. Bartlett, Henry F. Chambers, Neil O. Fishman, Anthony Harris, John H. Powers, III, L. Barth Reller, Lisa Saiman, and Brad Spellberg (also rapporteur); 2) for CDC, Drs. Lesley McGee, Arjun Srinivasan, and Cynthia G. Whitney; 3) for FDA, Drs. John Farley, Steven Gitterman, Sally Hojvat, Joseph Toerner, and Katherine Laessig; 4) for NIAID, Drs. Rose Aurigemma, Maureen Beanan, and Jane Knisely; and 5) pharmaceutical and diagnostics industry representatives, including Drs. Barry I. Eisenstein, Steve Gilman, Steven J. Projan, John H. Rex, Joyce Sutcliffe, Fred C. Tenover, and Barbara Zimmer.

IDSA's Board of Directors wishes to thank each of the individuals mentioned above as well as the paper's authors for their tireless commitment to find solutions to the antibiotic resistance and antibiotic pipeline problems. In particular, the Board wishes to acknowledge the efforts of Brad Spellberg and Robert Guidos in the development of this policy paper.

The authors would like to extend special thanks to Drs. Louis Rice and George Talbot for their careful review of the manuscript.

Potential conflicts of interest. B. S. has consulted for Pfizer, Basilea, The Medicines Company, Achaogen, Novartis, Cerexa, Trius, Nektar, Theravance, Meiji, Eisai, Anacor, and GlaxoSmithKline. He has received grant funding from the NIH, clinical trial grant support from Novartis, Astellas, Gilead, and Cubist, and owns equity in NovaDigm Therapeutics Inc.

M. B. is on Scientific Advisory Boards for Avidbiotics, Danon, Procter & Gamble, Adamas, Puretech, and has current research support from NIH, Dow Chemical, L'Oreal, Gates Foundation, and the Diane Belfer Program for Human Microbial Ecology. He serves on the Advisory Board for Clinical Research for NIH.

R. G. is an IDSA employee.

H. B. provided consultation for Basilea, Cerexa, Cubist, Durata, Merck (adjudication committee), Methylgene, J&J, Nabriva, Optimer, Rib-X, Targanta/TMC, Theravance, and Wyeth/Pfizer (data safety monitoring board) in the last 12 months.

J. B. employer, the University of California, has contracts for consulting with Johnson & Johnson, Trius, Bayer, Nabriva, Pfizer and Cerexa/Forest, and contracts for clinical trials with Johnson & Johnson, Cubist, and Trius.

B. I. E. is a full time employee of Cubist and also holds stock in Eli Lilly.

D. Gerding holds patents for the treatment and prevention of Clostridium difficile infection that are licensed to ViroPharma, is a consultant for ViroPharma, Optimer, Cubist, Merck, Pfizer, Hospira, Medicines Co, Astellas and Actelion, and has received research grants from GOJO, Merck, Optimer, Sanofi-Pasteur, Eurofins Medinet and ViroPharma.

R. L. has received grant funding through the US CDC.

L. B. R. has no conflicts to disclose.

J. R. is an employee and shareholder of AstraZeneca Pharmaceuticals.

D. S. has received grant funding from the US CDC.

E. S. is employed by Hospital Corporation of America (HCA, Inc.), is on the speaker bureau for Cubicin, Ethicon and Sage, and has received grant funding from AHRQ and CDC.

F. T. is an employee and shareholder of Cepheid, a molecular diagnostics company, and has received honoraria from the Association of Public Health Laboratories and the Washington Infectious Diseases Society.

D. Gilbert has consulted for Achaogen, Pfizer, Merck, and Advanced Life Sciences.

The paper's drafters possessed broad professional expertise across the spectrum of infectious diseases medicine. The pharmaceutical and diagnostics industry representatives, Drs. Eisenstein, Rex, and Tenover, are IDSA members, and their input was essential for understanding the broader implications of the paper's policy recommendations and warranted their being listed among the paper's drafters. The final policy recommendations adopted by IDSA's Board of Directors do not necessarily represent the opinions of the drafters or the organizations for which they work.

### GLOSSARY OF ABBREVIATIONS (Alphabetical)

 ABCs = Active Bacterial Core surveillance AHRQ = Agency for Healthcare Research and Quality AIC Fee = Antibiotic Innovation and Conservation Fee ARO = Antimicrobial Resistance Office ARSRN = Antimicrobial Resistance Surveillance and Research Network ASPR = Assistant Secretary for Preparedness and Response BARDA = Biomedical Advances Research and Development Authority CABP = community-acquired bacterial pneumonia CDC = Centers for Disease Control and Prevention CDER = Center for Drug Evaluation and Research CDRH = Center for Devices and Radiological Health CLSI = Clinical and Laboratory Standards Institute CMS = Centers for Medicare and Medicaid Services CPIS = clinical pulmonary infection score CRADA = Cooperative Research and Development Agreements DHHS = Department of Health and Human Services EARS-Net = European Antimicrobial Resistance Surveillance Network ESAC = European Surveillance of Antimicrobial Consumption ESBL = extended-spectrum beta lactamase ESKAPE = Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, and ESBL (Enterobacter and E. coli) ECDC = European Centre for Disease Prevention and Control EU = European Union FDA = Food and Drug Administration GAIN Act = Generating Antibiotic Incentives Now Act GMP = Good Manufacturing Practices GNB = Gram-negative bacilli (bacteria) HABP = hospital-acquired bacterial pneumonia HAIs = hospital-acquired infections IDSA = Infectious Diseases Society of America IND = investigational new drug MRSA = methicillin resistant Staphylococcus aureus NARMS = National Antimicrobial Resistance Monitoring System NHSN = National Health Safety Network NIAID = National Institute of Allergy and Infectious Diseases NIH = National Institutes of Health NPV = net present value PAMTA = Preservation of Antibiotics for Medical Treatment Act PDR = pan-drug resistant PHAAB = Public Health Antimicrobial Advisory Board PHEMCE = Public Health Emergency Medical Countermeasure Enterprise PK/PD = pharmacokinetic/pharmacodynamic PPP = public-private partnership R&D = research and development REMS = Risk Evaluation and Mitigation Strategies STAAR Act = Strategies to Address Antimicrobial Resistance Act USDA = US Department of Agriculture VABP = ventilator-associated bacterial pneumonia XDR = extremely drug resistant
 ABCs = Active Bacterial Core surveillance AHRQ = Agency for Healthcare Research and Quality AIC Fee = Antibiotic Innovation and Conservation Fee ARO = Antimicrobial Resistance Office ARSRN = Antimicrobial Resistance Surveillance and Research Network ASPR = Assistant Secretary for Preparedness and Response BARDA = Biomedical Advances Research and Development Authority CABP = community-acquired bacterial pneumonia CDC = Centers for Disease Control and Prevention CDER = Center for Drug Evaluation and Research CDRH = Center for Devices and Radiological Health CLSI = Clinical and Laboratory Standards Institute CMS = Centers for Medicare and Medicaid Services CPIS = clinical pulmonary infection score CRADA = Cooperative Research and Development Agreements DHHS = Department of Health and Human Services EARS-Net = European Antimicrobial Resistance Surveillance Network ESAC = European Surveillance of Antimicrobial Consumption ESBL = extended-spectrum beta lactamase ESKAPE = Enterococcus, Staphylococcus, Klebsiella, Acinetobacter, Pseudomonas, and ESBL (Enterobacter and E. coli) ECDC = European Centre for Disease Prevention and Control EU = European Union FDA = Food and Drug Administration GAIN Act = Generating Antibiotic Incentives Now Act GMP = Good Manufacturing Practices GNB = Gram-negative bacilli (bacteria) HABP = hospital-acquired bacterial pneumonia HAIs = hospital-acquired infections IDSA = Infectious Diseases Society of America IND = investigational new drug MRSA = methicillin resistant Staphylococcus aureus NARMS = National Antimicrobial Resistance Monitoring System NHSN = National Health Safety Network NIAID = National Institute of Allergy and Infectious Diseases NIH = National Institutes of Health NPV = net present value PAMTA = Preservation of Antibiotics for Medical Treatment Act PDR = pan-drug resistant PHAAB = Public Health Antimicrobial Advisory Board PHEMCE = Public Health Emergency Medical Countermeasure Enterprise PK/PD = pharmacokinetic/pharmacodynamic PPP = public-private partnership R&D = research and development REMS = Risk Evaluation and Mitigation Strategies STAAR Act = Strategies to Address Antimicrobial Resistance Act USDA = US Department of Agriculture VABP = ventilator-associated bacterial pneumonia XDR = extremely drug resistant

### Appendix B: RELEVANT STATEMENTS BY THE US SENATE APPROPRIATIONS COMMITTEE

#### The US Senate Appropriations Committee Stated in the 111th Congress:

“Antimicrobial Resistance—The Committee strongly urges the National Institute of Allergy and Infectious Diseases to devote additional resources to developing new antibacterial drugs. Priority bacteria include Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and ESBL positive bacteria such as E. coli and Enterobacter species, which cause the majority of healthcare-associated infections. Rapid diagnostic tests that support antibacterial clinical trials and antibiotics' appropriate use are also needed.

…Antibacterial resistance and the diminishing antibacterial pipeline are complex problems. Multi-pronged solutions are required to sufficiently limit the impact of antibacterial resistance on patients and the public and to spur the development of products to address antibacterial resistant infections. The Committee encourages the Assistant Secretary for Preparedness and Response and the National Institute for Allergy and Infectious Diseases to create a seamless approach to the research and development of new antibacterial drugs, particularly those designed to combat Gram-negative infections, which will help the transition across the spectrum of enterprise from basic research to product development and procurement.” [60]

#### With Respect to FDA Funding, the US Senate Agriculture Appropriations Subcommittee Stated:

“Antimicrobial Resistance—Antimicrobial resistance, and the resulting failure of antimicrobial therapies in humans, is a mounting public health concern.

Antibiotic Development—The Committee continues to be concerned about unresolved scientific issues regarding clinical development in the antibacterial drug arena, which has been identified as a serious impediment to new antibacterial development. In its report last year, the Committee directed FDA to issue clinical trial guidance for several serious indications. The Committee directs FDA to report [back to the Committee] by December 3, 2010, on its progress, including the status of FDA's work toward a final guidance on community-acquired bacterial pneumonia as well as how FDA plans to address guidance for multi-drug and pan-resistant organisms.

The Committee last year also encouraged FDA to identify ways to promote the development and/or appropriate use of priority antibacterial drugs for humans for which current market incentives are inadequate, by working with other governmental entities and interested parties to begin this work. The Committee directs FDA to address these issues in its December 2010 report, as well.” [61]

### Appendix C: AN OVERVIEW OF SUPERIORITY AND NON-INFERIORITY TRIALS OF ANTIBIOTICS

#### I. Background

There are two broad categories of clinical trials used to determine if a new drug should be approved by FDA: superiority trials and non-inferiority trials [100, 120, 121]. Complexities exist for execution and interpretation of both types of studies, particularly when applied to antibiotics for the treatment of serious or life-threatening infections.

#### II. Superiority Trials of Antibiotics

There are two major categories of superiority clinical trials [120, 121]. In one form, the experimental drug is compared with placebo (“placebo-controlled trial”). In the second form, the experimental drug is compared with another drug (“active-controlled trial”). A third study design, “historically-controlled” trials, may compare the experimental drug to either background medical care or to an active control, and are only acceptable for registrational trials (i.e., to support drug approval) under very strict conditions [98]. Historically-controlled trials are discussed briefly with active-controlled trials below.

##### A. Placebo-Controlled Superiority Trials of Antibiotics

Placebo-controlled superiority trials are ethical to conduct if: 1) there is no available therapy that is known to be effective for the disease being studied (i.e., there is “equipoise” regarding the benefit of any available therapy); or 2) if the disease being studied is unlikely to cause harm to the patient before effective rescue therapy can be provided if the patient's disease progresses while being treated with placebo [120]. The clear and substantial efficacy of antibiotics for serious and life-threatening bacterial infections, both in terms of lives saved and prevention of morbidity, precludes conduct of placebo-controlled trials for these infections (Table 3 and [53–55, 62, 118, 119, 122]). Furthermore, the rapidity of progression of typical bacterial infections precludes the use of effective escape therapy to prevent harm from patients being treated with placebo in most settings. One example of a setting in which placebo-controlled studies may be ethical to conduct for antibiotics is uncomplicated urinary tract infection. However, the established efficacy of antibiotic therapy for such infections makes enrollment of patients into such studies very difficult from a practical perspective, even if ethically acceptable. Thus, for most serious and life-threatening bacterial infections, placebo-controlled trials cannot be conducted.

##### B. Active-Controlled Superiority Trials of Antibiotics.

An experimental antibiotic that can kill bacteria resistant to a comparator antibiotic should have superior efficacy to that comparator antibiotic when treating patients infected with those resistant bacteria. However, in conducting an active-controlled clinical trial, the comparator antibiotic(s) must be selected so as to not deprive patients of available effective therapy. Therefore, active-controlled superiority trials of antibiotics are ethical to conduct only if: 1) the control (i.e., the comparator antibiotic) is active against most, or all, of the bacterial strains likely to be encountered in the study; OR 2) all available antibiotics that could be used as comparators for the study are inadequately active against the strains likely to be encountered, such that effective therapy is not being denied to patients; OR 3) effective rescue therapy can be instituted rapidly enough to preclude serious illness upon recognition that the strain causing the infection is resistant to the comparator drug (e.g., uncomplicated urinary tract infections).

The susceptibility (ability of antibiotics to kill the bacteria) of the disease-causing bacteria is almost never known at the time an infected patient is enrolled in a clinical trial evaluating initial antibiotic treatment. Therefore, the comparator drugs chosen for study in antibiotic clinical trials are selected because they are anticipated to be effective against all, or almost all, strains likely to be encountered during conduct of the study. Because antibiotic therapy is generally so effective when treating infections caused by susceptible bacteria, it is unlikely that an experimental antibiotic can achieve superiority to a marketed comparator antibiotic when the bacteria causing the infections under study are susceptible to both antibiotics. In most circumstances, such studies pose an unacceptable risk to the study sponsor of failing to show that that the experimental antibiotic is superior to the comparator antibiotic, even if the experimental antibiotic is, in fact, highly effective.

One scenario in which active-controlled superiority clinical trials of antibiotics are intuitively both ethical to conduct and can be reasonably expected to achieve superiority is the study of an experimental antibiotic with efficacy against PDR bacteria. Since no antibiotic is available that is effective to treat PDR bacteria, the experimental antibiotic would have a reasonable chance to show superiority if it was active against the target bacteria. The possible efficacy of the experimental antibiotic for treating infections caused by PDR pathogens raises questions about the ethics of randomizing patients in a pivotal study to the chance of treatment with an ineffective standard comparator regimen. However, a superiority study is ethical in this situation because: 1) the safety profile of the experimental drug is not established, while the safety profile of the comparator regimen is established; and 2) the efficacy of the experimental regimen is possible, but not yet definitively established.

It should also be possible to study infections caused by PDR bacteria in historically-controlled trials, such that all patients under active investigation in a trial are receiving experimental therapy, with objective outcomes compared to those achieved in historical controls treated with standard therapy in compliance with regulatory standards [98]. There are many practical barriers to conduct of superiority trials for antibiotics, underscoring IDSA's call for FDA to establish guidance on the conduct of such studies to standardize and clarify their appropriate design.

##### III. Non-Inferiority Clinical Trials of Antibiotics

Since superiority studies cannot be conducted for most serious infections, the only possible pathway to approval for many new antibiotics is the conduct of a “non-inferiority” clinical trial, which seeks to determine if the experimental antibiotic is similar in efficacy to a standard drug already on the market. For the last few years, FDA has been reconsidering the standards it uses to judge non-inferiority clinical trials. This re-evaluation of the regulatory standards for non-inferiority trials is the result of both a greater understanding of the statistical complexities underpinning the interpretation of results from non-inferiority trials [100, 120, 123–126], as well as intense public scrutiny in the aftermath of highly publicized post-approved drug failures, such as that of telithromycin [76, 127, 128], for which questions of safety and appropriateness of non-inferiority trial conduct were raised.

The fundamental statistical dilemma regarding interpretation of the results of non-inferiority trials relates to the fact that experimental drugs are not directly compared with placebo/no therapy in a non-inferiority study [98, 121]. Therefore, if the experimental drug is found to be “non-inferior” to the comparator drug, there are two possible statistical interpretations: 1) both drugs are superior to placebo for the disease under study, and the experimental drug should be approved by the regulatory agency; OR 2) neither drug is superior to placebo for the disease under study, and the reason why the drugs appear to have similar efficacy is that a similar placebo-effect is seen in both arms. Approval of the experimental drug under the latter scenario would result in marketing of an ineffective drug to the public.

The following is a simple logic flow that can be used to ensure that ineffective drugs are not approved as a result of successful non-inferiority studies:

• 1) If the comparator drug is known to be superior in efficacy to placebo from prior studies, AND

• 2) the experimental drug is similar in efficacy to the comparator drug, THEN

• 3) the experimental drug also must be superior in efficacy to placebo.

By this logic, non-inferiority clinical trials should only be used when the comparator drug has been previously shown to be superior to placebo. Unfortunately, this desire for previous randomized placebo-controlled trials, while logical, is also the fundamental underpinning for why antibiotic development, out of proportion to other drugs, has been so severely impacted by the current regulatory environment. Antibiotics were among the first effective drugs, and became available in the US in late 1936, fully two decades before randomized placebo-controlled trials came into widespread use [119, 129]. Thus, for virtually all serious infections, there are no randomized, placebo-controlled studies to precisely define how effective comparator antibiotics are, which makes problematic the design of modern non-inferiority studies for these diseases.

Nevertheless, as discussed in this policy paper, less sophisticated studies from the 1930s–1940s unequivocally document a massive survival benefit of antibiotics for serious bacterial infections (Table 3). Overall, the rate of death from infections in the US fell by ∼220 per 100,000 population during the first 15 years of the antibiotic era; that rate of death then fell only by a further ∼20 per 100,000 over the following 45 years, during which time all other advances in modern medicine (including critical care medicine) were achieved [62, 113]. There is no question that antibiotics are life-saving for serious bacterial infections.

It has also been argued that non-inferiority trials should not be conducted because what society needs are “better” drugs, not “non-inferior” drugs, to treat antibiotic-resistant infections. However, as discussed, patients in whom a new antibiotic is likely to be superior to an old antibiotic are those infected by bacteria resistant to the old drug. Such patients cannot ethically be enrolled in the clinical trial, since they cannot be randomized to a chance of receiving ineffective treatment. For example, when studying a new antibiotic with efficacy against MRSA, one cannot randomize patients infected with MRSA to a 50% chance of being treated with methicillin. Instead one has to compare a new antibiotic to an old antibiotic for the treatment of infections susceptible to both drugs. In these comparisons, the new drug is very unlikely to be superior to an effective old drug, making such studies impractical.

Sufficient data are available to ensure that comparator antibiotics used in non-inferiority studies for new antibiotics are massively more effective than placebo. Because antibiotics do have very large treatment effects for serious bacterial infections and because superiority studies of antibiotics are impractical in most cases, non-inferiority studies are relevant and necessary to support development and approvals of new antibiotics.

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## Author notes

*
This policy paper, written by Brad Spellberg, Martin Blaser, Robert J. Guidos, Helen W. Boucher, John S. Bradley, Barry I. Eisenstein, Dale Gerding, Ruth Lynfield, L. Barth Reller, John Rex, David Schwartz, Edward Septimus, Fred C. Tenover, and David N. Gilbert, was developed for and approved by the IDSA Board of Directors on February 9, 2011.
IDSA represents more than 9300 physicians, scientists and other health care professionals who specialize in infectious diseases. IDSA seeks to improve the health of individuals, communities, and society by promoting excellence in patient treatment and care, education, research, public health, and prevention relating to infectious diseases.