1 See Infectious Diseases Soc’y of Am., Bad Bugs No Drugs 3 (July 2004), http://www.idsociety.org/uploadedFiles/IDSA/Policy_and_Advocacy/Current_Topics_and_Issues/Advancing_Product_Research_and_Development/Bad_Bugs_No_Drugs/Statements/As%20Antibiotic%20Discovery%20Stagnates%20A%20Public%20Health%20Crisis%20Brews.pdf [http://perma.cc/7AA3-DC6M].

2 See, e.g., id. at 9 (“In a growing and frightening number of cases, these bacteria are resistant to many approved drugs, and patients have to be treated with new, investigational compounds or older, toxic alternatives. For many patients, there simply are no drugs that work.”).

3 In this Article, “antibiotic” refers to traditional small-molecule drugs used to treat bacterial infections. “Antibiotic resistance” means bacterial resistance to these small-molecule drugs and is the focus of this Article. The term “antibacterial product” includes a broader range of products to diagnose, prevent, and treat bacterial infections, including diagnostic tests, vaccines, and alternative therapies like bacteriophages and monoclonal antibodies. Finally, the term “antimicrobial resistance” encompasses not only bacterial resistance but also resistance to viruses, parasites, and mycobacterial infections like tuberculosis.

4 Widdus, Roy, Public-Private Partnership: An Overview, 99 Transactions Royal Soc’y Tropical Med. & Hygiene S1, S5 (2005)Google Scholar.

5 Tucker, Jonathan B., Developing Medical Countermeasures: From BioShield to BARDA, 70 Drug Dev. Res. 224, 225 (2009)Google Scholar.

6 See, e.g., President’s Council of Advisors on Sci. & Tech. (PCAST), Report to the President on Combating Antibiotic Resistance 40 (2014) (“The experience of product development partnerships for neglected diseases may provide useful insight in how to commercialize drugs with relatively less lucrative markets at close-to-marginal cost pricing.”); Spellberg, Brad et al., Combating Antimicrobial Resistance: Policy Recommendations to Save Lives, 52 Clinical Infectious Diseases (Supp. 5) S397, S398 tbl.1 (2011)Google ScholarPubMed (calling for new PPPs in addition to existing government-supported collaboratives to “supplement traditional industry R&D for critically needed antimicrobial drugs.”); Jaczynska, Ella et al., Business Model Options for Antibiotics Learning from Other Industries 22 (2015)Google Scholar, http://drive-ab.eu/wp-content/uploads/2014/09/Business-Model-Options-for-Antibiotics-learning-from-other-industries.pdf [http://perma.cc/7NT8-YJRF] (“Working groups in the EU, the US, the WHO and elsewhere should … explore a global PPP for antibiotics R&D …. The exact nature of this needs to be explored further with an understanding of the how this organizational model would drive the changes needed and achieve the desired impact.”).

7 Dep’t of Essential Med. & Health Prods., World Health Organization [WHO], Fostering the Development and Rational Use of Antibiotics: How a Product Development Partnership Could Promote Innovation and Responsible Access to Antibiotics 1 (2015), http://www.who.int/phi/implementation/Meeting_Report_WHO-DNDi_AMR_Technical_Consultation_final.pdf [http://perma.cc/NUZ8-YYVX].

8 See, e.g., Gupta, Ravindra K. et al., Global Trends in Antiretroviral Resistance in Treatment-Naive Individuals with HIV After Rollout of Antiretroviral Treatment in Resource-Limited Settings: A Global Collaborative Study and Meta-Regression Analysis, 380 Lancet 1250, 1250-51 (2012)Google Scholar (HIV); Klein, E. Y., Antimalarial Drug Resistance: A Review of the Biology and Strategies to Delay Emergence and Spread, 41 Int’l J. Antimicrobial Agents 311, 312 (2013)Google Scholar (malaria); Köser, Claudio U. et al., Drug-Resistance Mechanisms and Tuberculosis Drugs, 385 Lancet 305, 305-06 (2015)Google Scholar (tuberculosis).

9 A 2014 report from the World Health Organization (WHO) assessed global ABR surveillance infrastructure and concluded that there are “significant gaps in surveillance, and a lack of standards for methodology, data sharing and coordination” in all WHO regions. WHO, Antimicrobial Resistance: Global Report on Surveillance, at X (2014); see also Ctr. for Disease Dynamics, Econ., & Policy (CDDEP), The State of the World’s Antibiotics 24 (2015) (concluding that “[m]ore comprehensive data collection and systematic examination and dissemination of existing data are needed to complete the global picture of antibiotic resistance”).

10 For example, the WHO obtained national data for three types of bacteria (E. coli, K. pneumoniae and S. aureus) and found that the “proportion resistant to commonly used … antibacterial drugs exceeded 50% in many settings.” WHO, supra note 9, at 69. Another recent report concluded that resistance patterns “vary considerably between and within countries,” but reported increasing rates of resistance in many different types of bacteria in most countries reviewed. CDDEP, supra note 9, at 19.

11 Nordmann, Patrice et al., Global Spread of Carbapenemase-Producing Enterobacteriaceae, 17 Emerging Infectious Diseases 1791, 1791 (2011)Google Scholar; Papp-Wallace, Krisztina M. et al., Carbapenems: Past, Present, and Future, 55 Antimicrobial Agents & Chemotherapy 4943, 4943 (2011).Google Scholar

12 Carbapenems are effective against both Gram-positive bacteria (e.g., S. aureas and S. pneumoniae) and the Gram-negative bacteria (e.g., K. pneumoniae, P. aeruginosa, and E.coli). See Papp-Wallace, supra note 11, at 4946.

13 See id.

14 Colistin (a polymixin antibiotic), when available, is often used to treat carbapenem-resistant infections, but is known to have high nephrotoxicity. See, e.g., Falagas, Matthew E. & Rafailidis, Petros I., Editorial, Nephrotoxicity of Colistin: New Insight into an Old Antibiotic, 48 Clinical Infectious Diseases 1729, 1729 (2009)Google Scholar. Tigecyclin, another highly toxic antibiotic, is another rarely used last-resort option. See Livermore, David M., Tigecycline: What Is It, and Where Should It Be Used? 56 J. Antimicrobial Chemotherapy 611, 611 (2005)Google Scholar.

15 Though global surveillance remains incomplete, CRE has thus far been documented at high levels in the Americas, Europe and Asia. CDDEP, supra note 9, at 17 fig.1-3 (illustrating the percentage of cabapenem-resistant Klebsiella pneumoniae by country, from 2011-2014).

16 Ctr. for Disease Control & Prevention (CDC), Antibiotic Resistance Threats in the United States, 2013, at 21 (2013) (identifying CRE as one of the top three most urgent ABR threats).

17 Nordmann, supra note 11, at 1791.

18 Id. (“Enterobacteriaceae are the source of community- and hospital-acquired infections. They have the propensity to spread easily between humans (hand carriage, contaminated food and water) and to acquire genetic material through horizontal gene transfer, mostly by plasmids and transposons.”).

19 Id. at 1792. Experts are concerned that CRE may follow the pattern of other highly-resistant bacteria once primarily associated with hospitals but are now prevalent in the community, including community-acquired methicillin-resistant S.aureus (CA-MRSA) and extended-spectrum β-lactamase (ESBL)-producing E.coli. See David, Michael Z. & Daum, Robert S., Community-Associated Methicillin-Resistant Staphylococcus aureus: Epidemiology and Clinical Consequences of an Emerging Epidemic, 23 Clinical Microbiology Rev. 616, 619 (2010)Google Scholar; Doi, Yohei et al., Community-Associated Extended-Spectrum β-Lactamase–Producing Escherichia coli Infection in the United States, 56 Clinical Infectious Diseases 641, 641-42 (2013)Google Scholar.

20 Barlam, Tamar F. & Gupta, Kalpana, Antibiotic Resistance Spreads Across Borders, 43 J.L. Med. & Ethics 12, 13 (2015)Google Scholar.

21 See id. (noting that drinking water resources and pools of street water have tested positive for the bacteria). Enterobacteriaceae can transmit genetic material—including genes causing resistance—to other bacteria via mobile genetic elements called plasmids and transposons. Nordmann, supra note 11, at 1791.

22 CDC, Vital Signs: Carbapenem-Resistant Enterobacteriaceae, 62 Morbidity & Mortality Wkly. Rep. 165, 170 (2013)Google Scholar. The three classes of CRE most widely recognized as global threats are those expressing or harboring K. pneumoniae carbapenemases (or “KPC”), Metallo-β-Lactamases (e.g. New Delhi metallo-β-lactamase-1 or “NDM-1”), and oxacillinase (OXA)-48 Type enzymes. Papp-Wallace, supra note 11, at 4946.

23 E.g., CDC, supra note 16, at 11.

24 For example, in the U.S., resistance is estimated to incur $20 billion in direct costs and additional productivity losses of $35 billion (USD). Id. Meanwhile, the E.U. estimates $1.5 billion (EUR) in indirect costs annually. European Center for Disease Prevention & Control [ECDC], The Bacterial Challenge: Time to React, at viii (2009), http://ecdc.europa.eu/en/publications/Publications/0909_TER_The_Bacterial_Challenge_Time_to_React.pdf [http://perma.cc/86E3-2PFH].

25 CDDEP, supra note 9, at 26 (noting that between 2000 and 2010 total global antibiotic consumption grew by more than 30%, though most high-income countries maintained or decreased consumption).

26 Id. at 29 (noting that 20-50% of antibiotic use estimated to be inappropriate).

27 In many hospitals, even in advanced medical systems, antibiotics are often used a substitute for infection control practices. See, e.g., Cookson, Barry D., The Emergence of Mupirocin Resistance: A Challenge to Infection Control and Antibiotic Prescribing Practice, 41 J. Antimicrobial Chemotherapy 11, 15 (1998)Google Scholar (“Any agent should not be used as a substitute for poor infection control and antibiotic prescribing practices, but as part of an overall policy developed, audited and reviewed by the local relevant healthcare workers.”).

28 Wlodaver, Clifford G. & May, Christopher L., Why Do Physicians Unnecessarily Prolong Antibiotics?, 22 Infectious Diseases Clinical Prac. 318 (2014)Google Scholar.

29 See, e.g., Bonomo, Robert A., Multiple Antibiotic-Resistant Bacteria in Long-Term-Care Facilities: An Emerging Problem in the Practice of Infectious Diseases, 31 Clinical Infectious Diseases 1414, 1414 (2000)Google Scholar.

30 See, e.g., Means, Arianna Rubin et al., Correlates of Inappropriate Prescribing of Antibiotics to Patients with Malaria in Uganda, PLOS ONE, Feb. 2014, at 1 (2014)Google Scholar.

31 CDDEP, supra note 9, at 29.

32 See CDC, supra note 16, at 37.

33 CDDEP, supra note 9, at 38. Antibiotic use in agriculture is beyond the scope of this Article but is critical component of a comprehensive effort to combat ABR.

34 In late 2015, China reported a strain of E. coli containing a gene for resistance to the antibiotic colistin, a highly toxic drug reserved for when carbapenems fail. Liu, Yi-Yun et al., Emergence of Plasmid-Mediated Colistin Resistance Mechanism MCR-1 in Animals and Human Beings in China: A Microbiological and Molecular Biological Study, 16 Lancet 161, 162 (2016)Google Scholar. Bacteria containing this gene (called “mcr-1”) were found in isolates from food animals, and scientists demonstrated that the gene could transfer to other types of Enterobacter in both animals and humans. Id. Within weeks of the Chinese discovery, researchers from several European countries reported a similar finding, confirming fears that the gene would emulate the global mobility of the NDM-1 strain of CRE. Heidi Kornholt, New technology traces resistance gene quickly, Technical Univ. of Denmark (Dec. 3, 2015), http://www.dtu.dk/english/News/Nyhed?id=ff5ea50d-7c33-44a4-8be8-7cc52417deaf [http://perma.cc/LZF9-YXBX].

35 CDDEP, supra note 9, at 8-9 (summarizing patterns and trends in antibiotic resistance globally).

36 See Barlam & Gupta, supra note 20, at 13 fig.1; see also Laxminarayan, Ramanan et al., Antibiotic Resistance—the Need for Global Solutions, 13 Lancet 1057, 1058 (2014)Google Scholar (arguing that policy makers and scientists should coordinate to fight global antibiotic resistance); MacPherson, Douglas W. et al., Population Mobility, Globalization, and Antimicrobial Drug Resistance, 15 Emerging Infectious Diseases 1727, 1727 (2009)Google Scholar (explaining that risks associated with individuals constantly moving around the globe dangerously impact antimicrobial drug resistance). In addition, increasing urbanization, as well as a growing and aging world population, is expected to fuel the infectious disease burden globally in the coming decades. Dye, Christopher, After 2015: Infectious Diseases in a New Era of Health and Development, 369 Phil. Transactions Royal Soc’y B, May 12, 2014, at 4-5Google Scholar; see also U.N. Secretary-General, A Life of Dignity for All: Accelerating Progress Towards the Millennium Development Goals and Advancing the United Nations Development Agenda Beyond 2015, ¶ 94, U.N. Doc. A/68/202 (July 26, 2013) (emphasizing the need to address increasing urbanization, particularly in the form of ensuring future city dwellers have access to clean water and sanitation).

37 Mendelson, M., Role of Antibiotic Stewardship in Extending the Age of Modern Medicine, 105 S. Afr. Med. J. 414, 414 (2015)Google Scholar (“The use of antibiotics to prevent surgical site infection enables safe surgical procedures that would otherwise carry significant morbidity and mortality. Antibiotics form an integral part of the management of high risk patients, such as the critically ill in intensive care units, those who are immunosuppressed as a result of transplantation, chemotherapy or HIV, and those with a broad spectrum of bacterial infection – from sepsis to septic shock.”).

38 See, e.g., Teillant, Aude et al., Potential Burden of Antibiotic Resistance on Surgery and Cancer Chemotherapy Antibiotic Prophylaxis in the USA: A Literature Review and Modelling Study, 15 Lancet 1429 (2015)Google Scholar (“Increasing antibiotic resistance threatens the efficacy of these procedures and could result in adverse clinical outcomes, including increased rates of morbidity, or death.”).

39 Aminov, Rustam I., A Brief History of the Antibiotic Era: Lessons Learned and Challenges for the Future, Frontiers Microbiology, Dec. 8, 2010, at 4Google Scholar. More than twenty novel classes of antibiotics were introduced between the years 1930 and 1962. Coates, Anthony R. M. et al., Novel Classes of Antibiotics or More of the Same?, 163 Brit. J. Pharmacy 184, 184 (2011)Google Scholar.

40 Coates et al., supra note 39, at 184.

41 Spellberg, Brad, The Future of Antibiotics, 18 Critical Care 228, 229 (2014)Google Scholar.

42 Id.

43 Payne, David J. et al., Time for a Change: Addressing R&D and Commercialization Challenges for Antibacterials, 370 Phil. Transactions Royal Soc’y B, May 8, 2015, at 4Google Scholar (“The discovery challenges do not stop at identifying leads. The next step is the optimization of those leads to increase antibacterial activity and decrease safety and or tolerability issues…. [The] requirement for high doses and high exposures often results in high attrition for experimental antibacterials due to tolerability and safety problems.”).

44 Spellberg, supra note 41, at 229; see also Rex, John H. et al., The Evolution of the Regulatory Framework for Antibacterial Agents, 1323 Annals N.Y. Acad. Sci. 11, 12 (2014)Google Scholar (calling for the employment of a tiered framework to motivate increased antibacterial research).

45 For example, major drug regulatory authorities like the FDA require large phase III clinical trials and challenging trial designs that many observers argue make drug development for specific problem pathogens (e.g., P. aeruginosa) or specific types of emerging resistance (e.g., CRE) infeasible. Rex et al., supra note 44, at 12; see also Payne, supra note 43, at 6 (“Major health authorities have moved towards a more flexible approach, as reflected in the FDA 2013 Guidance for Antibiotics for Unmet Medical Needs, and the EMA’s 2013 Addendum, which discuss limited evidence of clinical efficacy/safety to support approval for treatment of infections caused by multidrug-resistant (MDR) organisms for which there are limited treatment options.”).

46 Although, a few antibiotics have achieved “blockbuster” status in recent years. See CDDEP, supra note 9, at 56 (“The combination of amoxicillin and clavulanic acid … had global sales of $2 billion [(USD)] in 2001.”); Press Release, Cubist Pharm., Inc., Cubist Announces Fourth Quarter/Full-Year 2013 Revenues; Provides Pipeline Update (Jan. 13, 2014, 7:30 AM), http://www.businesswire.com/news/home/20140113005717/en/Cubist-Announces-Fourth-QuarterFull-Year-2013-Revenues-Pipeline#.VgPnFt9Viko [http://perma.cc/LM6K-L2Q3] (reporting that Cubicin (daptomycin) had sales of over $1 billion (USD) in 2013).

47 Outterson, Kevin et al., Approval and Withdrawal of New Antibiotics and Other Antiinfectives in the U.S., 1980-2009, 41 J.L. Med. & Ethics 688, 692 (2013)Google Scholar.

48 See id. at 694.

49 See Rachel Zetts, The Pew Charitable Trusts, Antibiotics Currently in the Clinical Development Pipeline 1 (2015), http://www.pewtrusts.org/~/media/Assets/2015/03/AntibioticsInnovationProject_DataTable_March2015.pdf?la=en [http://perma.cc/FEH9-ZXYU] (noting that as of July 2015 36 new antibiotics are in clinical development for the United States market).

50 Aylin Sertkaya et al., Eastern Research Group, Inc. (ERG), Analytical Framework for Examining the Value of Antibacterial Products, at 3-11 (2014) (estimating average time to generic entry at ten to fourteen years).

51 Pull incentives promise a reward after a company successfully brings a new drug to market. Elias Mossialos et al., Policies and Incentives for Promoting Innovation in Antibiotic Research 5 (2010). For example, extending IP rights, market exclusivity, or data exclusivity for new antibiotics, promising large government procurements after product registration (i.e. advance market commitments), or awarding monetary prizes can all serve as an additional pull for innovators. Id. at 89–100. In the U.S., the Generating Antibiotic Incentives Now (GAIN) Act, enacted in 2012 as part of a larger statute, grants an additional five years of market exclusivity for new antibiotics designated under the law as a “qualified infectious disease product,” defined as “an antibacterial or antifungal drug for human use intended to treat serious or life-threatening infections.” Food and Drug Administration Safety and Innovation Act of 2012, Pub. L. No. 112-144, §§ 801-06 (2012) (commonly known as the GAIN Act or GAIN provisions). The extra five years of market protection is in addition to any existing exclusivity, including that which may be applicable under Hatch-Waxman (five years or three years), orphan drug (seven years), or pediatric exclusivity (six months). GAIN: How a New Law Is Stimulating the Development of Antibiotics, The Pew Charitable Trusts, (Nov. 7, 2013), http://www.pewtrusts.org/en/research-and-analysis/issue-briefs/2013/11/07/gain-how-a-new-law-is-stimulating-the-development-of-antibiotics [http://perma.cc/8ZYA-7PKD]. However, some have argued that standing alone this incentive is insufficient to drive significant new private investment into antibiotic R&D. See, e.g., Ambrose, Paul G., Antibiotic Bill Doesn't GAIN Enough Ground, 17 Nature Med. 722, 772 (2011)Google Scholar. “Lego-regulatory” incentives that assign priority review or fast track designation for particular product candidates also provide pull by shortening the time for clinical trials and regulatory review, thereby extending patent-protected market exposure. Mossialos et al., supra, at 100-06. For example, the U.S. priority review voucher (PRV) program was created by law in 2007 to provide incentives for drug manufacturers to invest in R&D for neglected diseases of global poverty and modified by Congress over the years to address rare pediatric diseases and emerging global threats like Ebola. Rachel Kiddell-Monroe et al., Univs. Allied for Essential Med., Re:Route; A Map of Alternative Biomedical R&D Landscape, at 46-48, 89 (2016). Companies pursuing drugs for these indications may qualify for a voucher that can be used to get a quick review on another, more lucrative drug, or sold to another company to use. Id. at 46-48. The program’s ultimate effectiveness in relation to Congress’ original goals is still subject to debate, but several companies have obtained and sold vouchers, indicating renewed interest in otherwise commercially unattractive drug targets. See, e.g., Kesselheim, Aaron S. et al., Experience with the Priority Review Voucher Program for Drug Development, 314 JAMA 1687, 1687 (2015)Google Scholar. In contrast, push incentives provide financial assistance earlier in the R&D process. Mossialos et al., supra, at 5. Direct grants and contracts to pharmaceutical companies for early research and clinical development, typically given by governments, is the most common push strategy. Id. Direct grants to pharmaceutical companies for early research and clinical development, typically given by governments or private foundations, is the most common push strategy. Joseph A. DiMasi & Henry G. Grabowski, Patents and R&D Incentives 16 (June 25, 2004) (unpublished manuscript) (on file with author). R&D tax credits are another example of a push approach; by offering financial incentives early in the drug discovery process, companies can better justify investments relative to expected return. Renwick, Matthew J. et al., A Systematic Review and Critical Assessment of Incentive Strategies for Discovery and Development of Novel Antibiotics, J. Antibiotics, Spring 2015, at 4Google Scholar.

52 Moran, Mary, A Breakthrough in R&D for Neglected Diseases: New Ways to Get the Drugs We Need, 2 PLOS MED. 828, 829 (2005)Google Scholar; Grabowski, Henry, Increasing R&D Incentives for Neglected Diseases: Lessons from the Orphan Drug Act, in International Public Goods and Transfer of Technology Under a Globalized Intellectual Property Regime 457, 472 (Maskus, Keith E. & Reichman, Jerome H. eds., 2005)Google Scholar.

53 See generally Renwick et al., supra note 51, at 1 (compiling a comprehensive catalogue of push and pull incentive proposals for antibiotic development).

54 For example, one advantage of pull mechanisms is that funders can “draw on the expertise of a large and diffuse set of researchers, rather than identifying and funding a handful with the greatest potential.” Grace, Cheri & Kyle, Margaret, Comparative Advantages of Push and Pull Incentives for Technology Development: Lessons for Neglected Disease Technology Development, 6 Global F. Update Res. for Health 147, 147 (2009)Google Scholar. Push incentives, on the other hand, are favored by some economists because of the higher realized value of early funding relative to future funding, the latter subject to “discounting” when pharmaceutical companies calculate the expected return on investment. Sertkaya et al., supra note 50, at 3-1.

55 Most experts generally agree that a mix or hybrid combination of push and pull incentives is ultimately needed to spur antibacterial product development. See, e.g., Chatham House Report, Towards a New Global Business Model for Antibiotics: Delinking Revenue from Sales 2, 6 (Charles Clift et al. eds., 2015) (“Given the nature of the R&D landscape, a successful outcome was likely to involve a combination of different approaches tailored to different stages of the innovation process and taking into account the very diverse nature of R&D and healthcare systems across countries.”); PCAST, supra note 6, at 41 (recommending that the federal government “rapidly analyze various options for attracting greater private investment in developing new antibiotics ….”); Outterson, Kevin et al., Repairing the Broken Market for Antibiotic Innovation, 34 Health Aff. 277, 283 (2015)Google Scholar (proposing three specific reforms to revitalize the antibiotic pipeline).

56 Hoffman, Steven J. & Outterson, Kevin, What Will it Take to Address the Global Threat of Antibiotic Resistance?, 43 J.L. Med. & Ethics 6, 7 fig.1 (2015)Google Scholar (illustrating and deeming this interrelationship a “policy tripod”).

57 Daulaire, Nils et al., Universal Access to Effective Antimicrobials: An Essential Feature of Global Collective Action Against Antimicrobial Resistance, 43 J.L. Med. & Ethics (Supp. I) 17, 17 (2015)Google Scholar.

58 Id. (highlighting that only 30% of children with suspected pneumonia in sub-Saharan Africa receive antibiotics).

59 See United Nations Children’s Emergency Fund (UNICEF), Amoxicillin Dispersible Tablets (DT): Product Profile, Availability and Guidance 1 (2011), http://www.unicef.org/supply/files/Amoxicillin_DT_Product_Profile_and_Supply_Update.pdf [http://perma.cc/J67Y-K8ZG].

60 Id. at 5.

61 See, e.g., Cars, Otto, Securing Access to Effective Antibiotics for Current and Future Generations. Whose Responsibility?, 119 Upsala J. Med. Sci. 209, 209 (2014)Google Scholar (“Lack of access to and affordability of newer antibiotics are other critical factors associated with ABR in LMICs.”).

62 International trade agreements serve to further protect IP rights from generic competition in LMICs and can therefore limit access. See, e.g., Shah, Aakash Kaushik, The Ethics of Intellectual Property Rights in an Era of Globalization, 41 J.L. Med. & Ethics 841, 847 (2013)Google Scholar.

63 De George, Richard T., Intellectual Property and Pharmaceutical Drugs: An Ethical Analysis, 15 Bus. Ethics Q. 465, 476 (2005)Google Scholar. While some claim that IP rights laws enjoy a moral and ethical justification because they drive innovation to meet a social needs, countervailing rights-based claims (i.e. the right to life, adequate healthcare, access to essential lifesaving drugs, and the obligation to aid those in need) and justice- or fairness- based claims (e.g. distributive justice, social justice) challenge the status quo argument that the social benefits IP protections trump access-related harms. Id. at 466.

64 Chatham House Report, supra note 55, at 18.

65 De George, supra note 63, at 474 (arguing that access “requires that [they] be transported, distributed, and administered to patients”).

66 Bigdeli, Maryam et al., Access to Medicines from a Health System Perspective, 1 Health Pol’y & Plan. 1, 2 (2012)Google Scholar (noting that sub-standard medicines are a contributing factor of antimicrobial resistance).

67 In the context of antibiotic resistance, for example, training and equipping health workers for the proper diagnosis and treatment of resistant bacterial infections is a critical systems-level intervention, as is building trust between health workers and patients. See id. at 2-3. Both have direct implications for access to appropriate antibiotics. See id. (observing that “interconnections between systems components are frequently ignored”); see also Behdinan, Asha et al., Some Global Policies for Antibiotic Resistance Depend on Legally Binding and Enforceable Commitments, 42 J.L. Med. & Ethics 68, 68 (2015)Google Scholar (“Development assistance is still necessary for health systems strengthening. Strong health systems are the back-bone of reducing the global threat of ABR.”).

68 Defining “appropriate” antibiotic use is challenging, but for purposes of this Article means choosing the right indication, dose, duration, and route of administration to maximize clinical care or prevention of infection while limiting collateral damage of antibiotic use, including toxicity, selection of pathogenic organisms, and the emergence of resistance. Dellit, Timothy H. et al., Infectious Diseases Society of America and the Society for Healthcare Epidemiology of America Guidelines for Developing an Institutional Program to Enhance Antimicrobial Stewardship, 44 Clinical Infectious Diseases 159, 162 (2007)Google Scholar; see also Millar, Michael, Can Antibiotic Use Be Both Just and Sustainable … or Only More or Less So?, 37 J. Med. Ethics 153, 155 (2010)Google Scholar (defining appropriate antibiotic use as use “justified by evidence of benefit (or good reasons to believe that there will be a benefit) to an individual or others (who may or may not be identifiable)”).

69 Vaccines not only protect against potentially-resistant bacterial infections (e.g. invasive pneumococcal disease) but also reduce antibiotic use by preventing both bacterial and non-bacterial infections for which antibiotics are commonly—and often inappropriately—consumed. See, e.g., Nat’l Vaccine Advisory Comm., A Call for Greater Consideration for the Role of Vaccines in National Strategies to Combat Antibiotic-Resistant Bacteria 11-12 (2016); Callaway, Ewen, Hidden Bonus from Vaccination: Immunization Against Pneumococcus in Africa Also Reduces Levels of Antibiotic Resistance, 512 Nature 14, 14 (2014)Google Scholar.

70 Hospital infection control programs that include hygiene protocols (e.g. handwashing, patient isolation and contact precautions, and surface decontamination) can prevent emergence of highly-resistant bacteria and control outbreaks when they occur. Sandora, Thomas J. & Goldman, Donald A., Preventing Lethal Hospital Outbreaks of Antibiotic-Resistant Bacteria, 367 New Eng. J. Med. 2168, 2168 (2012)Google Scholar. Although infection control practices have improved in rich countries over the last few decades, they are rare in LMICs. See, e.g. Raka, Lul, Prevention and Control of Hospital-Related Infections in Low and Middle Income Countries, 4 Open Infectious Diseases J. 125, 126 (2010)Google Scholar (“Although many hospitals in the LMIC may have infection control programmes [sic] and committees on paper, in practice they barely exist.”). In advanced health systems, antibiotics are also used prophylactically to prevent postsurgical infections (therefore reducing the likelihood of ABR infections). Bratzler, Dale W. & Houck, Peter M., Antimicrobial Prophylaxis for Surgery, 189 Am. J. Surgery 395. 395 (2005)Google Scholar. However, in many LMICs antibiotics are often used after surgery at higher doses and for longer durations relative to preoperative administration, which increases both costs and risk of ABR. See CDDEP, supra note 9, at 35.

71 See Sandora & Goldman, supra note 70, at 2168.

72 Bauer, Karri A. et al., Review of Rapid Diagnostic Tests Used by Antimicrobial Stewardship Programs, 59 Clinical Infectious Diseases (Supp. 3) S134, S134–S135 (2014)Google Scholar.

73 See, e.g., Bebell, Lisa M. & Muiru, Anthony N., Antibiotic Use and Emerging Resistance: How Can Resource-Limited Countries Turn the Tide?, 9 Global Heart 347, 349 (2014)Google Scholar.

74 CDDEP, supra note 9, at 29.

75 Id.

76 Id. at 26, 28; see also Laxminaryan, supra note 36, at 1060 (“Although carbapenems are expensive, sales in Egypt, India, and Pakistan have increased with over-the-counter availability.”).

77 CDDEP, supra note 9, at 26 (noting that growth in retail carbapenem sales was particularly steep in India, Pakistan, and Egypt, though it is possible that they were prescribed in hospitals and filled at a pharmacy).

78 Mendelson, Mark et al., Maximising Access to Achieve Appropriate Human Antimicrobial Use in Low-Income and Middle-Income Countries, 387 Lancet 188, 188 (2016)Google Scholar (describing the challenge of “balancing access and excess”).

79 Id. at 190 (“Prescription-only regulation might not be practical for countries with inadequate health delivery systems with few qualified prescribers, and might restrict appropriate access to antimicrobials. In such settings, strengthening capacity of community pharmacists and other health workers to make good decisions on dispensing antimicrobials (ie, [sic] appropriate use) through education, feasible evidence-based algorithms, and guidelines is crucial, as are community involvement and education.”).

80 Millar, supra note 68, at 154, 155. But see Anomaly, Jonny, Combating Resistance: The Case for a Global Antibiotics Treaty, 3 Pub. Health Ethics 13, 18 (2010)Google Scholar (“[N]obody has the right—not even the poor—to inflict uncompensated harms on other people against their will … [and] there is no obligation … to make antibiotics as cheap and available as they are today. The main obligation is rather to make antibiotics expensive enough to curb low value consumption and encourage the development of new treatments in order to protect innocent parties.”).

81 The ethical groundwork for balancing antibiotic conservation and access is still developing, but ethicists generally agree that there is a strong moral and ethical justification for conservation under certain circumstances. See Millar, supra note 68, at 154; Jasper Littmann, Antimicrobial Resistance and Distributive Justice (February 2014) (unpublished manuscript) (on file with author) (showing that the “restriction of antibiotic use can be justified”); Millar, Michael, Constraining the Use of Antibiotics: Applying Scanlon’s Contractualism, 38 J. Med. Ethics 465, 468 (2012)Google Scholar (applying Scanlon’s contractual approach as a principle to decide when antibiotic use “will ameliorate some substantial risk”).

82 See, e.g., Chatham House Report, supra note 55, at 4.

83 See, e.g., id.

84 See, e.g., Nat’l Vaccine Advisory Comm., supra note 69, at 11; Caliendo, Angela M. et al., Better Tests, Better Care: Improved Diagnostics for Infectious Diseases, 57 Clinicial Infectious Diseases (Supp. 3) S139, S163 (2013)Google Scholar; Czaplewski, Lloyd et al., Alternatives to Antibiotics–A Pipeline Portfolio Review, 16 Lancet Infectious Diseases 239, 240 (2016)Google Scholar.

85 For example, nontraditional therapies like bacteriophages will likely require new clinical development and regulatory pathways as well as manufacturing processes, which could reduce the attractiveness of these products in the eyes of the private sector investors. See, e.g., Czaplewski, supra note 84, at 246 (“Innovative therapies might need innovative regulation.”).

86 Thadani, Khushbu B., Public Private Partnership in the Health Sector: Boon or Bane, 157 Soc. & Behav. Sci. 307, 309 (2014)Google Scholar.

87 Reich, Michael R., Public-Private Partnerships for Public Health, in Public-Private Partnerships for Public Health 8 (Reich, Michael R. ed., 2002)Google Scholar.

88 Id. at 3. In their article on global partnerships, Buse and Walt expand on these basic components, outlining characteristics of strong partnerships: (1) clearly specified, realistic and shared goals; (2) clearly delineated and agreed roles and responsibilities; (3) distinct benefits for all parties; (4) the perception of transparency; (5) active maintenance of the partnership; (6) equality of participation; (7) meeting agreed obligations. Buse, K. & Walt, G., Global Public-Private Partnerships: Part II – What are the Health Issues for Global Governance?, 78 Bulletin of WHO 699, 704 (2000)Google Scholar.

89 The first PPP addressing infectious diseases was the International AIDS Vaccine Initiative (IAVI), established in 1996, and the first drug development PPP, Medicines for Malaria Venture, was founded in 1999. See Widdus, supra note 4, at S5. Mahoney marked the year 2000 as the beginning of the “Era of Partnerships.” Mahoney, Richard T., Product Development Partnerships: Case Studies of a New Mechanism for Health Technology Innovation, 9 Health Res. Pol’y & Sys. 33, 34 (2011)Google Scholar.

90 The Mectizan Donation Program is one example of a successful partnership between the pharmaceutical company Merck, the WHO, and other not-for-profit entities to distribute drugs to treat two NTDs, onchocerciasis and lymphatic filariasis. History, Mectizan Donation Program, http://www.mectizan.org/about/history [http://perma.cc/D8MK-E88E]. The International Trachoma Initiative is another well-known partnership between Pfizer, the WHO, and the Edna McConnell Clark Foundation to distribute the drug Zithromax for the blinding NTD trachoma. See Reich, Michael R., Public-Private Partnerships for Public Health, 6 Nature Med. 617, 618–19 (2000)Google Scholar.

91 Widdus, Roy, Public-Private Partnerships for Health: Their Main Targets, Their Diversity, and Their Future Directions, 79 Bulletin of WHO 713, 717 (2001)Google Scholar (but noting that most of these programs “use products that are curative and relatively easy to administer in that few doses are required”).

92 Reich, supra note 90, at 617.

93 Reich, supra note 87, at 6. For a detailed account of Gavi’s origins, see Muraskin, William, The Last Years of the CVI and the Birth of the GAVI, in Public-Private Partnerships for Public Health, supra note 87, at 115Google Scholar.

94 For an analysis of Gavi’s co-financing strategy, see Saxenian, Helen et al., An Analysis of How the GAVI Alliance and Low- and Middle-Income Countries Can Share Costs of New Vaccines, 30 Health Aff. 1122, 1130-31 (2011)Google Scholar.

95 WHO Maximizing Positive Synergies Collaborative Group, An Assessment of Interactions Between Global Health Initiatives and Country Health Systems, 373 Lancet 2137, 2154Google Scholar (“Gavi [has] been consistent in identifying the health workforce as an important constraint in the delivery of services.”).

96 Gavi Matching Fund, GAVI, http://www.gavi.org/funding/matching-fund/ [http://perma.cc/BT5D-QRDQ].

97 International Finance Facility for Immunisation, GAVI, http://www.gavi.org/funding/IFFIm/ [http://perma.cc/Y9PL-PXMK]; see also Mark Pearson et al., Evaluation of the International Finance Facility for Immunisation (IFFIm) 5 (2011), http://www.gavi.org/results/evaluations/iffim-evaluation/ [http://perma.cc/V7DN-3A9H].

98 International Finance Facility for Immunisation, supra note 97.

99 In June 2009, the governments of Italy, the United Kingdom, Canada, the Russian Federation, and Norway, along with the Bill & Melinda Gates Foundation, collectively pledged a total of $1.5 billion (USD) to fund a pilot AMC against pneumococcal disease. See Gavi, Advance Market Commitment for Pneumococcal Vaccines Annual Report9 (2015).

100 See, e.g., Birn, Anne-Emanuelle & Lexchin, Joel, Beyond Patents: The GAVI Alliance, AMCs and Improving Immunization Coverage Through Public Sector Vaccine Production in the Global South, 7 Human Vaccines 291 (2011)Google Scholar (arguing that Gavi’s use of the AMC wrongly accepts that the patent system is the best method for increasing global vaccine coverage); Light, Donald W., Saving the Pneumococcal AMC and GAVI, 7 Human Vaccines 138, 140 (2011)Google Scholar (criticizing Gavi’s use of the AMC to promote existing pneumococcal vaccines developed for rich countries, rather than to stimulate development of new vaccines targeted at pneumococcal strains burdening LMICs).

101 The New Global Framework to support expansion of MDR-TB services and care, WHO (2015), http://www.who.int/tb/challenges/mdr/greenlightcommittee/en/ [http://perma.cc/FHP4-6HR6].

102 Gupta, Rajesh et al., Increasing Transparency in Partnerships for Health–Introducing the Green Light Committee, 7 Tropical Med. & Int’l Health 970, 970 (2002)Google Scholar.

103 The Global Drug Facility negotiates discount prices for drugs from pharmaceutical companies, but these drug companies are not considered core partners of the GLC. Id. at 974.

104 Id. In 2011, in response to stakeholder criticism of the GLC as being too controlling of access to second-line drugs, GLC leadership agreed to “shift from a controlling to a supporting mode,” by decentralizing GLC to regional centers and providing more technical assistance. See WHO, Meeting Report of the Global GLC Committee 4 (2011), http://www.who.int/tb/challenges/mdr/greenlightcommittee/Meetingreport1stgGLCmeeting.pdf [http://perma.cc/MA36-SUWB].

105 Some PDPs, including Aeras and IAVI, do operate their own manufacturing and research facilities. Clinical Research Centers, Int’l AIDS Vaccine Initiative (2015), http://www.iavi.org/what-we-do/science/clinical-research-centers [http://perma.cc/4SG6-MV33].

106 Widdus, supra note 4, at S5, S7.

107 Id.

108 According to Commission on Macroeconomics and Health (CMH) categories, “Type II” diseases like HIV, TB, and hepatitis are those primarily affecting low- and middle-income countries and for which treatments exist but are out of reach, and “Type III” diseases like NTDs are those that affect mainly poor countries and lack treatment options. Comm’n on Macroeconomics & Health, WHO, Macroeconomics and Health: Investing in Health for Economic Development 16 (2001). In contrast, “Type I” diseases affect both rich and poor countries with limited treatment options. Id. Plahte and Røttingen categorize antibiotic resistant bacterial infections as a Type I disease. Plahte, Jens and Røttingen, John-Arne, Antibiotic Innovation—Some Lessons from the WHO Processes on Public Health, Innovation, and Intellectual Property, in AMR Control 2015: Overcoming Global Antimicrobial Resistance 19 (2014)Google Scholar.

109 For example, IAVI includes 10 vaccine candidates for HIV. See IAVI Portfolio, Int’l AIDS Vaccine Initiative (2015), http://www.iavi.org/what-we-do/science/iavi-portfolio [http://perma.cc/XRY3-6QCL]. In contrast, the Drugs for Neglected Diseases Initiative (DNDi) portfolio includes over 25 treatments and combination therapies for several neglected disease, including Human African Trypanosomiasis (HAT), Leishmaniasis, Chagas, Malaria, pediatric HIV, Filarial diseases, including onchocerciasis (river blindness) and lymphatic filariasis (elephantiasis), mycetoma, and Hepatitis C. DNDi Portfolio December 2015, Drugs for Neglected Diseases initiative (2015), http://www.dndi.org/diseases-projects/portfolio.html [http://perma.cc/LEH6-YWFY].

110 Widdus, supra note 4, at S5.

111 Id.

112 Id.

113 Some global health PDPs have more than one board if incorporated in more than one country. Interview with Matt Doherty, Manager, Donor and Stakeholder Relations, Medicines for Malaria Venture (MMV), Geneva, Switz. (Aug. 28, 2015). Some countries will not give to foreign organizations unless they have a distinct legal entity in one of their countries. Interview with Benjamin Alsdurf, Manager, External Affairs, TB Alliance, in Wash., D.C. (Sept. 1, 2015).

114 See, e.g., Buse, K. & Walt, G., Global Public-Private Partnerships: Part I–A New Development in Health?, 78 Bulletin of WHO 549, 550 (1999)Google Scholar (observing that PDPs engage in activities that “transcend[] national boundaries”).

115 One recent exception is the Global Health Innovative Technology (GHIT) Fund, a not-for-profit partnership between the Japanese government, Japanese pharmaceutical companies, the United Nations Development Program, and the Bill and Melinda Gates Foundation. See Slingsby, B.T. & Kurokawa, Kiyoshi, Commentary, The Global Health Innovative Technology (GHIT) Fund: Financing Medical Innovations for Neglected Populations, 1 Lancet e184, e184 (2013)Google Scholar.

116 For example, in 2015 the DNDi board included a representative from the Malaysia Ministry of Health and the Medicines for Malaria Venture (MMV) North Americas Board included a representative from the U.S. Agency for International Development (USAID). Board of Directors, Drugs for Neglected Diseases initiative (2016), http://www.dndi.org/about-dndi/our-people/board-directors/ [http://perma.cc/X77L-5ZKF]; MMV North America Inc. Board, Med. for Malaria Venture (2016), http://www.mmv.org/about-us/organization-and-governance/mmv-north-america-inc-board [http://perma.cc/ZE3C-V5ZE].

117 See, e.g., Widdus, supra note 4, at S5 (“Public-private partnerships for product development with a portfolio of candidate products at different stages can routinely replace those that have been terminated.”).

118 Id. at S4; see also Bishai, David M., et al., Product Development Partnerships Hit Their Stride: Lessons from Developing a Meningitis Vaccine for Africa, 30 Health Aff. 1058, 1058 (2011)Google Scholar (“Many of the current [product development] partnerships were started by the Bill & Melinda Gates Foundation, which had invested more than $1.9 billion in them as of 2009 and now funds seventeen of them.”).

119 See, e.g., Bishai et al., supra note 118, at 1061 (“The number of [private, corporate, and government] partners in the Meningitis Vaccine Project grew over time ….”).

120 Compare Interview with Jennifer Katz, Senior Advisor, Drugs for Neglected Disease Initiative (Aug. 28, 2015) (stating that DNDi makes an effort to keep a fifty-fifty split between public and private donors, and to keep all donors at twenty-five percent or below of the total funding base) with Int’l AIDS Vaccine Initiative, A World Without AIDS (Dec. 31, 2014), https://www.iavi.org/annual_reports/2014/ [http://perma.cc/NF5P-LZP9] (reporting sixty-nine percent of funding from governments).

121 See Interview with Jennifer Katz, supra note 120; see also Chatham House Report, supra note 55, at ix (“Various proposals have been put forward for international mechanisms to provide pooled funding for health-related actions that mainly meet the needs of LMICs.”).

122 See, e.g., Interview with Matt Doherty, supra note 113 (reporting that MMV uses an “all of the above” approach to economic incentives for advancing R&D).

123 See, e.g., Interview with Sylvie Fonteilles-Drabek, Head of Legal Dep’t, Med. for Malaria Venture (Oct. 15, 2015) (stating MMV negotiates terms related to sharing financial rewards should a candidate product qualify for a Priority Review Voucher).

124 See, e.g., Interview with Benjamin Alsdurf, supra note 113 (stating that TB Alliance agreements always include terms to ensure that any products borne out of the partnership are “adopted, available, and affordable”).

125 See, e.g., Medicines for Malaria Venture, MMV and Intellectual Property Rights (June 1, 2007) (“When they work together in a given research programme [sic], MMV and its partners decide on an appropriate strategy for managing existing and developed IPR. Such a strategy includes whether IP generated under the programme [sic] should be the subject of a patent application or should be dedicated to the public domain.”).

126 Id.

127 See, e.g., id. (stating the general terms of exclusivity, royalties, and transferability of MMV intellectual property licenses); see also Interview with Jennifer Katz, supra note 120 (stating that because most PDPs do not manufacture “in-house” licensing rights, they must be transferable to external partners in order to ensure manufacturing and distribution).

128 See Interview with Matt Doherty, supra note 113 (stating that most PDPs maintain legal departments in house, in part due to the complexity of the IP negotiating process); see also; Interview with Sylvie Fonteilles-Drabek, supra note 123 (stating that legal and business development departments from several PDPs meet annually to discuss concepts and strategies around partnering).

129 See Innovative Medicines Initiative, Strategic Research Agenda for Innovative Medicines Initiative 2, at 9 (2014); U.S. Dep’t Health & Human Servs., BARDA Strategic Plan 2011-2016, at 4 (2011).

130 Pandemic and All-Hazards Preparedness Act of 2006, 42 U.S.C. § 247d-7e (2012) (defining Medical Countermeasures (MCM) as therapeutics, vaccines, diagnostics, and other medical devices including ventilators)

131 U.S. Dep’t Health & Human Servs., supra note 129, at 4.

132 Id. at 5 (“BARDA fulfills its mission by supporting advanced research and development of needed medical countermeasures; working in collaboration with manufacturers, the NIH, the CDC, the FDA, and the Departments of Defense (DoD) and Homeland Security (DHS); supporting technology innovation through strategic initiatives; and overseeing Project BioShield acquisitions.”); see also Eichberg, Michael J., Public Funding of Clinical-Stage Antibiotic Development in the United States and European Union, 13 Health Security 156, 157 (2015)Google Scholar (noting that BARDA funding “may be applied to virtually any technical aspect of development, including clinical trials, microbiology and animal studies, manufacturing development, and regulatory costs”).

133 Joe Larsen, Deputy Dir., Biomedical Advanced Research & Dev. Auth, Presentation to the President’s Council of Advisors on Science and Technology (Mar. 27, 2015) (on file with author).

134 BARDA Guiding Principles, U.S. Dep’t Health & Human Servs. (Aug. 19, 2013) http://www.phe.gov/about/barda/stratplan/Pages/barda-guiding-principles.aspx [http://perma.cc/UE87-EPHB].

135 See Billington, John K., The ABCs of the US Broad Spectrum Antimicrobials Program: Antibiotics, Biosecurity, and Congress, 13 Health Security 349, 350-51 (2015)Google Scholar.

136 Joe Larsen, Deputy Dir., Biomedical Advanced Research & Dev. Auth, Presentation to United States Stakeholder Forum on Antimicrobial Resistance (August 20, 2015) (on file with author).

137 See Billington, supra note 135, at 350.

138 See U.S. Dep’t Health & Human Servs., 2014 Public Health Emergency Medical Countermeasures Enterprise (PHEMCE) Strategy and Implementation Plan 14 (2014) (“Calendar year 2013 brought to an end the first chapter of the Project BioShield program, which was initiated in 2004 with the passage of the Project BioShield Act and the advanced appropriation of the $5.6 billion [Special Reserve Fund].”); see also U.S. Dep’t Health & Human Servs., supra note 129, at 5 (drawing from the Special Reserve Fund to “support[] innovation through strategic initiatives and investment in technologies and research tools that facilitate countermeasure development”).

139 See DiMasi, Joseph A et al., The Price of Innovation: New Estimates of Drug Development Costs, 22 J. Health Econ. 151, 181 (2003)Google Scholar.

140 Eichberg, supra note 132, at 164.

141 See, e.g., The Competition in Contracting Act of 1984, 10 U.S.C. §2304 (2012); Patent and Trademark Law Amendments (Bayh-Dole) Act of 1980, 35 U.S.C. §§ 200–12 (2012); Contract Disputes Act of 1978, 41 U.S.C. §§ 7101-109 (2012). The “march-in” provision of the Bayh-Doyle Act implemented via the FAR regulation authorizes the government to take any IP created during the partnership forward if the company abandons the partnership or technology at issue. 35 U.S.C. § 203(1); see also Eichberg, supra note 132, at 163 (“With respect to collaborators, a contractor must specifically allow subawardees that are not-for-profits or small businesses to retain license to the IP they develop, subject to Bayh-Dole terms.”); Interview with Joe Larsen, Deputy Dir., Biomedical Advanced Research & Dev. Auth., in Arlington, Va. (June 25, 2015).

142 See Eichberg, supra note 132, at 157, 160 tbl.1.

143 Id. at 161.

144 Id. at 163.

145 Interview with Joe Larsen, supra note 141.

146 Press Release, U.S. Dep’t Health & Human Serv, HHS Forms Strategic Alliance to Develop New Antibiotics; Approach Provides a Pipeline of New Drugs Rather than a Single Medical Countermeasure (May 22, 2013), http://www.phe.gov/Preparedness/news/Pages/strategic-alliance-130522.aspx [http://perma.cc/4AZY-9ET8].

147 Id. (“HHS will provide $40 million for the 18-month agreement and up to a total of $200 million if the agreement is renewed for the full five years…. GSK researchers will conduct safety and toxicology testing, clinical pharmacology studies, clinical studies, and non-clinical studies to support approval to treat illnesses caused by bioterrorism agents like anthrax, plague and tularemia, as well as address antibiotic resistance.”).

148 HHS Enters into Strategic Alliance to Accelerate New Antibiotic Development, U.S. Dep’t Health & Human Serv., (Sept. 16, 2015), http://www.hhs.gov/news/press/2015pres/09/20150916a.html [http://perma.cc/Z5FF-EDT7].

149 Id.

150 The Project BioShield Act of 2004, 42 U.S.C. § 243 (2012) (authorizing post-commercialization agreements and spending funds on acquiring vaccines and other MCMs for biological threats).

151 See U.S. Dep’t Health & Human Servs., supra note 138, at 50. But see U.S. Dep’t Health & Human Servs., Postmarketing Studies and Clinical Trials — Implementation of Section 505(o)(3) of the Federal Food, Drug, and Cosmetic Act 3 (2011) (“Section 505(o)(3) authorizes FDA to require certain postmarketing studies and clinical trials for prescription drugs approved under section 505(b) of the Act and biological products approved under section 351 of the PHS Act.”).

152 Small Business Program, Nat’l Inst. of Allergy & Infectious Diseases (2016), https://www.niaid.nih.gov/researchfunding/sb/Pages/default.aspx [http://perma.cc/42V7-4XT7].

153 Kamel, N. et al., The Innovative Medicines Initiative (IMI): A New Opportunity for Scientific Collaboration Between Academia and Industry at the European Level, 31 Eur. Respiratory J. 924, 924 (2008)Google Scholar.

154 The IMI Funding Model, Innovative Med. Initiative (2010), http://www.imi.europa.eu/content/imi-funding-model [http://perma.cc/B9TG-E7MA].

155 See Projects, Innovative Medicines Initiative (2010), http://www.imi.europa.eu/content/ongoing-projects [http://perma.cc/5XWP-RYSS].

156 Innovative Med. Initiative, Fiction vs Facts: Setting the Record Straight 1-2 (2015).

157 Rex, John H., Commentary, ND4BB: Addressing the Antimicrobial Resistance Crisis, 12 Nature Revs. Microbiology 231, 231 (2014)Google Scholar (explaining “TRANSLOCATION” and “COMBACTE” as the two primary research projects by the IMI).

158 See Eichberg, supra note 132, at 159 (“ND4BB funding focuses almost exclusively on clinical-trial and related expenses.”).

159 AstraZeneca, IMI Launches New “New Drugs 4 Bad Bugs” Projects, Lab Talk (July 9, 2013), http://www.labtalk.astrazeneca.com/collaboration/imi-launches-new-new-drugs-4-bad-bugs-projects/ [http://perma.cc/9TZX-YQNX].

160 See Renwick, supra note 51, at 2 (noting that DRIVE-AB, a subsidiary program within the ND4BB initiative, aims to develop effective economic models for antibiotic development).

161 Kostyanev, T. et al., The Innovative Medicines Initiative’s New Drugs for Bad Bugs Programme: European Public-Private Partnerships for the Development of New Strategies to Tackle Antibiotic Resistance, 71 J. Antimicrobial Chemotherapy 290, 291 (2015)Google Scholar.

162 Id.

163 The People Pay, Corporations Cash In: Problems Plague EU Medical Research Initiative, Spiegel Online Int’l (Apr. 1, 2015), http://www.spiegel.de/international/europe/imi-in-eu-project-citizens-count-corporations-cash-in-a-1025550.html [http://perma.cc/YVT4-RSXY].

164 Eichberg, supra note 132, at 162 (“Within IMI there is very little involvement by government personnel in the day-to-day management of a project or in major milestone decisions. Written reports on technical progress are required infrequently, such as once a year. There is a process for formal interim evaluations performed by a set of independent experts, but the IMI website currently indicates these happen once, 2 years after a project starts. Key development milestone decisions are made by the coordinating EFPIA company.”).

165 However, for the purposes of enabling a consortia of multiple parties with varying levels interest in (or familiarity with) IP rights, the IMI provides overarching principles for IP rights and data sharing relating to new IP created during the course of the partnership. IMI Intellectual Property Policy, Innovative Meds. Initiative (2007), https://ec.europa.eu/research/participants/portal/doc/call/fp7/imi-ju-03-2010/30831-imi-ipr-policy01august2007_en.pdf [http://perma.cc/P28P-FHD5]; see also Eichberg, supra note 132, at 163 (noting that “all of these terms can be modified under the consortium agreement governing a particular project” and because consortia partners may change the terms of these agreements at will each agreement varies by project). Moreover, most IMI projects occupy a “precompetitive” collaborative environment where two or more pharmaceutical companies agree to invest jointly in early stage projects even though they compete against each other in the commercial Goldman, market. M., The Innovative Medicines Initiative: A European Response to the Innovation Challenge, 91 Clinical Pharmacology & Therapeutics 418, 419 (2012)Google Scholar (noting that private sector partners entering precompetitive agreements are typically large companies). Because precompetitive activities typically do not provide a direct commercial advantage, IMI partners do not risk losing IP rights by participating in a given project. Id. (noting that precompetitive activities may include development and qualification of biomarkers for drug efficacy or drug safety and of new knowledge-management strategies to exploit large data sets).

166 Plahte & Røttingen, supra note 108, at 19 (noting that, besides geographical differences, Type I diseases differ from Types II and III diseases by the nature of their market failure).

167 See, e.g., PCAST, supra note 6, at 40 (“The experience of product development partnerships for neglected diseases may provide useful insight in how to commercialize drugs with relatively less lucrative markets at close- to- marginal cost pricing.”).

168 Dep’t of Essential Med. & Health Prods., supra note 7, at 3.

169 Id. at 6.

170 Id.

171 G7 Germany, Declaration of the G7 Health Ministers: Berlin Declaration on Antimicrobial Resistance–Global Union for Antibiotics Research and Development (GUARD) 1, 5 (2015), http://www.ip-watch.org/weblog/wp-content/uploads/2015/10/G7-Health-Ministers-Declaration-AMR-and-EBOLA-final-Scan-mit-Unterschriften.pdf [http://perma.cc/92UQ-8JC6].

172 Id. at 10.

173 Interview with Carolyn Shore, Officer, The Pew Charitable Trusts, in Washington, D.C. (Jan. 8, 2016). Although this new partnership would incorporate input from drug developers to ensure quick translation of early discovery into public health outcomes, its primary goal is to support the foundational science required for antibacterial drug discovery. Id.

174 Id.

175 Id.

176 The term “PDP+” has been used previously by the World Health Assembly to describe a proposal for a new fund to assist global health PDPs financially. Martin Enserink, Another Global Health Fund? Here's Why, Science (May 19, 2010, 3:52 PM), http://www.sciencemag.org/news/2010/05/another-global-health-fund-heres-why [http://perma.cc/P94K-QSR2]. In that case, the “+” meant financial supplementation. Id. Here, the “+” means additional attributes beyond those of existing PDPs to address the unique needs of ABR.

177 Government partners could play a leadership role but decision making would be shared among both public and private partners, Japan’s Global Health Innovative Technology (GHIT) Fund. See About the GHIT Fund: Council, GHIT Fund, https://www.ghitfund.org/about/governance/council [http://perma.cc/AU9C-DVXV].

178 These secondary partnerships could be modeled on the Green Light Committee. See supra Part IV.A.1.

179 Bishai, supra note 118, at 1062 (“[T]he project’s flexibility allowed it to break down the development process into distinct components and recruit a team of partners whose special skills might not have come together for any other purpose. Each partner maintained its independence, and the project’s relationship with each one could be separately configured to maximize the chances of success.”).

180 Id. at 1061 (identifying success factors for the MenAfriVac project); see also Buse, Kent & Harmer, Andrew M., Seven Habits of Highly Effective Global Public–Private Health Partnerships: Practice and Potential, 64 Soc. Sci. & Med. 259, 268 (2007)Google Scholar (“[P]artnership is about engaging in external relationships and investing in them a variety of commitments.”).

181 See, e.g., DNDi, Partnerships to Bridge Innovation and Access; 2014 Annual Report 1, 61, http://www.dndi.org/wp-content/uploads/2009/03/DNDi_AR_2014.pdf [http://perma.cc/S6E7-S8TU].

182 International Finance Facility for Immunisation, supra note 97.

183 This will require depth of expertise that may require more than one partnership working together in a network, or “lattice” structure, within the same overarching model. See, e.g., Bishai, supra note 118, at 1061.

184 Plahte & Røttingen, supra note 108, at 21 (“We believe public funds should be used to finance innovation models that source R&D efforts from a multitude of commercial and noncommercial entities, much like the operational procedures for many of the Product Development Partnerships (PDPs).”).

185 See, e.g., id. (“[C]ontrolling IP rights to new antibiotics can be a key instrument for effective stewardship, at least in the short to medium term, i.e. the duration of the patent protection.”).

186 See Jaczynska et al., supra note 6, at 11 (“The current crisis in antibiotics has taken decades to emerge, and AMR will need to be addressed continually over further decades, in view of which the funding solution must be stable over long periods of time. Moreover, a regular stream of new antibiotics is required to replace the old ones as resistance builds. The time lag from bench to bedside is at least a decade and sometimes much longer. Human capital, such as university research teams, physicians, scientists, expertise in the private sector specializing in infectious diseases, and clinical trial networks, cannot be rebuilt quickly and it needs long-term stability.”).

187 See, e.g., Davies, Julian & Davies, Dorothy, Origins and Evolution of Antibiotic Resistance, 74 Microbiology & Molecular Biology Rev. 417, 428 (2010)Google Scholar.

188 DiMasi, Joseph A. et al., The Price of Innovation: New Estimates of Drug Development Costs, 22 J. Health Econ. 151, 153 (2003)Google Scholar (detailing average time for drugs to advance from discovery to market).

189 Jaczynska et al., supra note 6, at 36-38.

190 See, e.g., HHS Enters into Strategic Alliance to Accelerate New Antibiotic Development, supra note 148; see also, Nathan, Carl, Cooperative Development of Antimicrobials: Looking Back to Look Ahead, 13 Nature Rev. Microbiology 651, 656Google Scholar (“All these experiments in cooperative antimicrobial development demonstrate the effectiveness of open labs where scientists and physicians from governments, universities, other not-for-profit organizations and industry share knowledge, skills, methods, risks and rewards to work collaboratively. The key factors that these projects have in common are that each project involved or involves international and interdisciplinary participation and each engaged or engages both for-profit and not-for-profit institutions.”); After More than a Decade of Effort and Achievements, DNDi Hands Over Malaria Programme to MMV, DNDi (June 9, 2015), http://www.dndi.org/media-centre/news/2175-dndi-mmv-handover-statement.html [http://perma.cc/GEQ2-2RXQ] (reporting MMV and DNDi agreement to transfer two malaria products developed by DNDi and its partners over to the Medicines for Malaria Venture (MMV) Access and Product Management team).

191 See Reich, supra note 90, at 618 (noting that partnership “involve both ‘big p’ Partners, who assume core responsibilities for the joint enterprise, and ‘little p’ partners, whose participation is necessary for successful implementation”).

192 See Jaczynska, supra note 6, at 31 (recommending that a global antibiotics public-private partnership (GAPP) should be “a sustainable, independent and self-funding operation”).

193 National and global financial downturns can significantly impact the funding base allocation. For example, as a result of the global financial downturn of 2008, IAVI saw reductions in public sector funding in 2009. See IAVI, 2009 Annual Progress Report 35 (2010); Interview with IAVI staffer, in N.Y.C., N.Y. (Sept. 3, 2015).

194 As not-for-profit entities, most existing PDPs can advocate in public forums, though some statutory limitations apply. Interview with Erin Will Morton, Director, Global Health Technologies Coalition at PATH, in Washington, D.C. (Sept. 17, 2015). In the U.S., the Global Health Technologies Coalition (GHTC) represents a broad group of PDPs in front of Congress and U.S. agencies. Id. GHTC promote policies and funding to advance global health R&D. Id. Because GHTC advocates for the “entire pot” of global infectious disease threats rather than specific diseases, a new PDP focusing on ABR could conceivably join this platform as a member. Id.

195 Bishai, supra note 118, at 1061.

196 Reich, supra note 87, at 10.

197 Only India and China consume more antibiotics than the United States. See CDDEP, supra note 9, at 34.

198 The principle of common but differentiated responsibility is rooted in international law and commonly associated with global action on climate change. See, e.g., Wiley, Lindsay F., Moving Global Health Law Upstream: A Critical Appraisal of Global Health Law as a Tool for Health Adaptation to Climate Change, 22 Geo. Int’l Envtl. L. Rev. 439, 488 (2010)Google Scholar (“The principle of ‘common but differentiated responsibility’ … essentially means that ‘while all countries must join in efforts to reduce emissions of greenhouse gasses that contribute to climate change, the developed countries are required … to take the lead.’”).

199 See, e.g., Guh, Alice Y. et al., Epidemiology of Carbapenem-Resistant Enterobacteriaceae in 7 US Communities, 2012-2013, 314 JAMA 1479, 1480 (2015)Google Scholar (highlighting that “[i]n the United States, much of the initial dissemination of CRE can be attributed to organisms producing … a type of … enzyme that confers resistance to carbapenem antimicrobials”); Gupta, Neil et al., Carbapenem-Resistant Enterobacteriaceae: Epidemiology and Prevention, 53 Clinical Infectious Diseases 60, 60 (2011)Google Scholar (noting the increasing reports of CRE in the United States over the last decade).

200 Toner, Eric et al., Antimicrobial Resistance Is a Global Health Emergency, 13 Health Security 153, 154 (2015)Google Scholar.

201 Of the forty-one antibacterial candidates identified by Pew Charitable Trusts as either recently approved or currently in the pipeline, nearly half were sponsored by U.S.-based companies. See Antibiotics Currently in Clinical Development, The Pew Charitable Trusts (Dec. 2015), http://www.pewtrusts.org/~/media/assets/2015/12/antibiotics_datatable_201512.pdf [http://perma.cc/BJR3-VJYY] (providing a data table containing a list of the companies producing antibiotics).

202 See, e.g., Press Release, Merck, Merck Completes Tender Offer to Acquire Cubist (January 21, 2015), http://www.mercknewsroom.com/news-release/corporate-news/merck-completes-tender-offer-acquire-cubist [http://perma.cc/2VJE-FGMZ].

203 In January 2016, many of these companies signed a declaration calling on governments to work with industry to “develop new and alternative market structures that provide more dependable and sustainable market models for antibiotics, and to commit the funds needed to implement them.” Declaration by the Pharmaceutical, Biotechnology and Diagnostics Industries on Combating Antimicrobial Resistance, Review on Antimicrobial Resistance (Jan. 21, 2016), http://amr-review.org/industry-declaration [http://perma.cc/75FB-B7SQ]. Importantly, the declaration includes commitments to promote access and conservation. See id. (“These mechanisms are needed to … support antibiotic conservation … [and] [i]mprove access to high-quality antibiotics for all.”).

204 Exec. Order No. 13676, 79 C.F.R. 56931, 56934 (2014).

205 See The White House, National Action Plan for Combating Antibiotic-Resistant Bacteria 40 (2015) [hereinafter CARB Plan], https://www.whitehouse.gov/sites/default/files/docs/national_action_plan_for_combating_antibotic-resistant_bacteria.pdf [http://perma.cc/HK8M-2AJ7].

206 Id. at 47. The BARDA portfolio agreement with Astra Zeneca meets one of the early milestones in the plan and also demonstrates BARDA’s willingness to collaborate with other PDPs like the IMI’s ND4BB. See id. at 55. The CARB plan directs U.S. agencies to “explore collaborations with the New Drugs 4 Bad Bugs (ND4BB) programs of the Innovative Medicines Initiative.” Id.

207 Id. at 47.

208 See id. at 46 (describing how this working group was convened in response to the “critical” nature of economic incentives to developing antibiotics). Although the working group presented a report to the President in March 2015, it was never released publicly and there has been no indication from the White House that it will move forward with any of the report’s proposals.

209 Id. at 48.

210 In designing the incubator proposal, BARDA researched and drew from several existing PPP models, including state-run small business incubators and venture capital-based “evergreen” scientific discovery investment funds. See Joe Larsen, Deputy Director, BARDA Div. of CBRN Med. Countermeasures, Presentation to the President’s Advisory Council for CARB: BARDA’s Role in Combating Antimicrobial Resistance, at slide 6, 8. (September 29, 2015) (on file with author) (presenting the incubator concept and models to support it).

211 See id. at slide 7 (presenting a proposal for an incubator process).

212 Interview with Joe Larsen, supra note 141.

213 See U.S. Dep’t. Health & Human Servs., Public Health and Social Services Emergency Fund: Justification of Estimates for Appropriations Committees, Fiscal Year 2016, at 63 (2015) http://www.hhs.gov/sites/default/files/budget/fy2016/fy2016-public-health-social-services-emergency-budget-justification.pdf [http://perma.cc/H4AV-LFRY] (providing a budget summary in the table outlining appropriated funds and enacted funds for 2015, and requested funding by the President for BARDA, and specifically, for CARB).

214 Press Release, The White House, Office of the Press Sec’y, Fact Sheet: President’s 2016 Budget Proposes Historic Investment to Combat Antibiotic-Resistant Bacteria to Protect Public Health (Jan. 27, 2015), https://www.whitehouse.gov/the-press-office/2015/01/27/fact-sheet-president-s-2016-budget-proposes-historic-investment-combat-a [http://perma.cc/VH4L-6P5B]. While a president’s budget proposal in no way guarantees federal appropriations from Congress, it does serve as a starting point (though often the high-water mark) for congressional funding negotiations.

215 Compare Consolidated Appropriations Act, 2016, Pub. L. No. 114-113, 129 Stat. 2242, 2618 (allocating funding to the Public Health and Social Services Emergency Fund, “of which $511,700,000 shall remain available through September 30, 2017, for expenses necessary to support advanced research and development pursuant to section 319L of the PHS Act and other administrative expenses of the Biomedical Advanced Research and Development Authority”), with U.S. Dep’t. Health & Human Servs., supra note 213 (providing appropriated funding levels for FY2015 at approximately $415 million excluding specifically allocated Ebola funding).

216 Prescription-only laws may play an important role in LMICs where not already in place, though the effectiveness of this approach has been questioned. See CDDEP, supra note 9, at 29 (noting that such laws are not always enforced).

217 Revenue from this fee, also called an antibiotic innovation and conservation fee, could be used to promote further innovation or to implement antibiotic stewardship programs.

218 See Chatham House Report, supra note 55, at 3-4 (discussing the importance of delinkage).

219 See id., at 9-10, 26 (suggesting that “if a company were to bring a powerful new antibiotic to market, it would negotiate post-registration rewards contracts with various countries, but each of those contracts could also restrict antibiotic marketing and promotional activities by the company globally” and further suggesting that such prize amounts be based on costs associated with drug development, health impact, and social value).

220 See Mossialos et al., supra note 51, at 95–100 (describing various approaches to AMCs and their application).

221 See generally Marinissen, Maria Julia et al., Strengthening Global Health Security by Developing Capacities to Deploy Medical Countermeasures Internationally, 12 Biosecurity & Bioterrorism: Biodefense Strategy, Prac., & Sci. 284 (2014)Google Scholar (describing MCM deployment in response to the 2009 H1N1 influenza pandemic, and the lessons learned).

222 Despite a promising FY2016 funding increase for BARDA’s antibiotics program, it is not guaranteed that Congress will continue support a departure from BARDA’s core mission to protect the U.S. from biothreats in subsequent appropriations cycles. The President’s Executive Order, supra note 204, does not change the underlying statutory language defining BARDA’s core mission and qualifying pathogens—only Congress can do that. Some congressional leaders have warned BARDA from straying from its mission. See Hearing on Medical and Public Health Preparedness and Response Before the Comm. on Health, Educ., Labor & Pensions,114th Cong. (2015) (statement of Sen. Richard Burr) (explaining to BARDA director Robin Robinson that “BARDA’s work in [antibiotics] is tied to its overall work to advance medical countermeasures against CBRN threats, and not outside of this context”); see also Billington, John K., The ABCs of the U.S. Broad Spectrum Antimicrobials Program: Antibiotics, Biosecurity, and Congress, 13 Health Security 349, 349 (2015)Google Scholar (explaining that “the US Congress, which controls BARDA’s purse strings, has not universally embraced antibiotic resistance as a biodefense priority”).

223 In its 2014 report to the White House, PCAST proposed a new antibiotic incentive fund “to provide advanced market commitments and milestone payments to reward developers with later stage projects.” PCAST, supra note 55, at 6. However, the 2015 CARB Plan did not include this recommendation. See CARB Plan, supra note 205, at 46-47 (noting that “[e]conomic incentives for product development are critical” yet proposing only non-monetary support from the government).

224 Robert Weinstein, Professor of Internal Med., Rush Univ. Med. Ctr., National and International Efforts to Reduce Antibiotic Resistance, Presentation at IDWeek, San Diego, CA (Oct. 9, 2015) (on file with author).

225 Organized stakeholder advocacy will be needed to sustain political will for ABR. In 2014, the Infectious Diseases Society of America (IDSA) convened a new stakeholder coalition called the U.S. Stakeholder Forum on Antimicrobial Resistance (S-FAR) to build support for CARB plan implementation and to hold the federal government accountable for the CARB commitments. See U.S. Stakeholder Forum on Antimicrobial Resistance (S-FAR), Infectious Diseases Soc’y Am. (2015), http://www.s-far.org [http://perma.cc/6RGJ-XZ2T].

226 U.S. institutions have been major supporters of programs to address other forms of antimicrobial resistance (i.e. HIV, tuberculosis, and malaria), including programs to develop new therapeutics and diagnostics for drug resistant organisms. See supra Part IV (exploring PPP models for infectious disease prevention and control).

227 However, the Bill & Melinda Gates Foundation recently expressed interest in expanding its antimicrobial resistance portfolio. See Novel Approaches to Characterizing and Tracking the Global Burden of Antimicrobial Resistance, Bill & Melinda Gates Found. (Sept. 8, 2015), http://gcgh.grandchallenges.org/challenge/novel-approaches-characterizing-and-tracking-global-burden-antimicrobial-resistance-round [http://perma.cc/CD8H-X2T7 ] (“There is an unmet need in the generation and dissemination of high-quality evidence describing the impact of resistant organisms ….”).

228 At the WHO and DNDi stakeholder meeting held in December 2014 “[i]t was agreed that it was important to draw upon lessons learned from current PDPs, but that the nature of the antibiotics challenge required an updated, innovative model different from the classic PDPs for neglected diseases.” WHO, supra note 7, at 4. Others at the WHO and DNDi stakeholder meeting “felt that it would be misleading to label such an initiative a ‘PDP’ due to the inherent differences in function from the PDPs that currently exist in other areas.” Id. at 5.

229 Tim Smedley, Is it fair to accuse the pharma industry of neglecting tropical diseases?, Guardian (U.S.) (Oct. 15, 2015), http://www.theguardian.com/sustainable-business/2015/oct/15/pharma-industry-neglecting-tropical-diseases-snake-bite [http://perma.cc/UBX9-NUG8] (citing Novartis’ decision to hand over its compound library to TB Alliance and shut down its own NTD R&D program).

230 PDPs can claim progress in terms of new collaborations formed and new technologies brought to market, and access PPPs have effectively demonstrated increases in vaccine and therapeutic coverage among those in need. However, as Buse observed in his analysis of early PPP models, there is a need to “learn more about what makes a partnership ‘effective’ and in particular, what organizational forms and management arrangements represent best practice for governance, accountability and representation, and what factors contribute to partnership effectiveness on the ground.” Buse & Walt, supra note 88, at 708. One reason this research is difficult to conduct is the heterogeneity incumbent on any effort to solve a global health problem. As Reich observed in his early survey of PPPs for health, “[t]he nature of the disease and the treatment, the markets and profits of the products, the political context, the positions of governments, the economic and social costs—all make a difference in the capacity of public-private partnerships to achieve results.” Reich, supra note 87, at 6. Some organizations have formed to assess PPP performance, including the Initiative on Public-Private Partnerships for Health (IPPPH) (launched in 2000, now inactive), the U.K.-based PDP Funders Group (led by major government PDP donors), and the Australia-based Policy Cures “G-Finder” tool, which monitors global investments in the development of pharmaceuticals for neglected diseases. See generally Widdus, supra note 4 (reporting on behalf of the IPPPH).

231 See Buse & Harmer, supra note 180, at 270 (proposing a “simple assessment mechanism … to score [global public-private health partnerships] on a biennial basis on their performance across a range of indicators”); Gunn, Magda et al., Correspondence, Benchmarking the Scientific Output of the Innovative Medicines Initiative, 33 Nature Biotechnology 811, 811 (2015)Google Scholar (proposing benchmarking criteria to measure scientific output of the E.U. Innovative Medicines Initiative).

232 See Outterson et al., supra note 55, at 284 (arguing that “[c]ountries acting in isolation can have only a limited impact on antibiotic resistance”).