American Journal of Law & Medicine

A New Product Development Partnership Model for Antibiotic Resistance

Antibiotics have prevented countless deaths from common infections and have made possible many modern medical procedures. Over the past few decades, antibiotic-resistant bacteria have become a global threat, spreading between healthcare facilities and throughout communities worldwide at an alarming pace. Antibiotic overuse and misuse in humans, animals, and the environment accelerate resistance by selecting for bacteria with antibiotic-resistant traits, which then become predominant and infect others. Meanwhile, few antibiotics remain active against the most resistant bacteria. There is an urgent need for new antibiotics and other antibacterial products to replace second-line and last resort therapies when they no longer work. This Article proposes a new U.S.-based, non-governmental, not-for-profit product development partnership (PDF) model specifically designed for antibacterial development. This new model should both supplement and complement existing government-led efforts and should be built with mechanisms in place to balance the values of innovation, access, and conservation.

I.   INTRODUCTION
II.  THE GLOBAL BURDEN OF ANTIBIOTIC RESISTANCE
III. NEW BUSINESS MODELS ARE NEEDED FOR INNOVATION, ACCESS,
     AND CONSERVATION
     A. BALANCING INNOVATION WITH ACCESS AND CONSERVATION
        1. Access
        2. Conservation
     B. LOOKING BEYOND ANTIBIOTICS
IV.  PUBLIC-PRIVATE PARTNERSHIP MODELS FOR INFECTIOUS DISEASE
     PREVENTION AND CONTROL
     A. PUBLIC PRIVATE PARTNERSHIPS FOR GLOBAL HEALTH
        1. Access PPPs
        2. Global Health Product Development Partnerships
     B. EXISTING PUBLIC-PRIVATE PARTNERSHIP MODELS FOR ANTIBIOTIC
        RESISTANCE
        1. The United States' Efforts to Adapt the PDP Model for ABR:
           The U.S. Broad Spectrum Antimicrobials Program
        2. European Union Efforts to Adapt the PDP Model for ABR: New
           Drugs Bad Bugs
V.   A NEW PDP MODEL FOR ABR
     A. CURRENT EFFORTS TO EXPLORE A NEW PDP MODEL FOR ABR
        1. World Health Organization/Drugs for Neglected Diseases
           Initiative Collaboration
        2. The Pew Charitable Trusts Roadmap for Antibiotic Discovery
     B. A PRODUCT DEVELOPMENT PARTNERSHIP "PLUS" MODEL FOR
        ANTIBACTERIALS
              1. Flexibility
              2. Adaptability
              3. Compatibility
              4. Sustainability
     C. AN OPPORTUNITY FOR UNITED STATES LEADERSHIP
        1. The United States Has Both the Moral Responsibility and the
           Technological Capacity to Lead Global Antibiotic Development
        2. Recent American Public Policy Actions Present a Window of
           Opportunity.
IV.  BUILDING THE PDP+
     A. PRACTICAL ACCESS AND CONSERVATION STRATEGIES
     B. OTHER CHALLENGES FACING THE PDP+
VII. CONCLUSION

I. INTRODUCTION

Antibiotics are one of medicine's most important advances. Since their discovery in the early twentieth century, they have prevented countless deaths from common infections and have made possible many modem medical procedures. (1) However, antibiotic-resistant bacteria are spreading between healthcare facilities and throughout communities worldwide at an alarming pace, killing an increasing number of patients and leaving some survivors with devastating, life-long disabilities. Hospitalized patients with multiple conditions, or comorbidities, are particularly vulnerable to these infections, as are immuno-compromised patients, such as transplant recipients, neonates, certain surgical patients, and cancer patients. Increasingly, however, healthy people outside the hospital are also at risk, as demonstrated by rising rates of difficult to-treat skin infections and urinary tract infections. Antibiotic overuse and misuse in humans, animals, and the environment accelerate resistance by selecting for bacteria with antibiotic-resistant traits, which then become predominant and infect others. Meanwhile, few antibiotics remain active against the most resistant bacteria. Resistance to second-line and last resort antibiotics is particularly concerning as patients are left with riskier treatment options if any at all. (2)

There is an urgent need for new antibiotics to replace second-line and last resort therapies when they no longer work. (3) Equally important is the need for policies to conserve the effectiveness of both existing and new antibiotics, and to ensure that patients who need these drugs have access to them. Many large pharmaceutical companies have left the antibiotics market for lack of commercial interest, and some observers have called for strong economic incentives and new business models to bring them back. However, any new economic incentive policy or business model to promote innovation must also incorporate mechanisms to ensure both conservation and access. Moreover, research and development ("R&D") pursuits must continue to expand beyond traditional small molecule antibiotics to include vaccines, diagnostics, and alternative therapies (hereafter "antibacterial" products).

Product development partnerships ("PDPs") for infection prevention and control were originally created to stimulate R&D for products that prevent and treat infections primarily burdening poor countries, including neglected tropical diseases ("NTDs"), HIV, tuberculosis, and malaria. (4) These partnerships have successfully developed products that otherwise may not have been developed on the commercial market. More recently, the United States and the European Union have adopted the PDP model to help overcome scientific barriers to drug discovery and to develop other socially valuable products, including medical countermeasures ("MCMs") for potential biothreats like anthrax and pandemic influenza." These government-led partnerships have also demonstrated that the PDP model holds promise for antibacterial product development. While PDPs are frequently mentioned in the literature as a possible solution to the antibiotic resistance ("ABR") problem,6 there is no in-depth assessment of their potential value as applied to antibacterial products. Recognizing this gap. the World Health Organization ("WHO") recently agreed to explore the need for a new global antibiotics development partnership. (7)

This Article proposes a new U.S.-based, non-governmental, not-for-profit PDP model specifically designed for antibacterial development. This new model should both supplement and complement existing government-led efforts and should be built with mechanisms in place to balance the values of innovation, access, and conservation. Part II summarizes the global burden of antibiotic resistance, with a focus on one of the most concerning global threats, carbapenem-resistant Enlerobacteriaceae ("CRE"). Part III describes the challenge of balancing innovation policies for new antibiotics with principles of access and conservation. Part IV reviews existing PDP and product access models for global health. Finally, Part V describes some basic attributes of a new PDP model for ABR and argues that the United States should lead the efforts to build it.

II. THE GLOBAL BURDEN OF ANTIBIOTIC RESISTANCE

While drug resistance to other global infectious diseases like tuberculosis, malaria, and HIV is well documented (referred to generally as "antimicrobial resistance"), (8) the global human health burden of ABR is poorly quantified because diagnostic and surveillance capabilities are inadequate in most countries. (9) Despite these gaps, available data suggest that ABR is widespread globally. (10) The emergence of carbapenem resistance illustrates the global scale of the ABR problem. Carbapenems are antibiotics that are administered intravenously and typically used as a last resort. (11) They have a broad spectrum of antibacterial activity compared with most other antibiotics (i.e. they kill more kinds of bacteria), (12) but they also carry significant safety risks. They can damage the kidneys and nervous system, disrupt the body's immune response, and change the natural intestinal microflora, potentially selecting for carbapenem-resistant bacteria. (13) As such, physicians avoid using them unless there are no other options. (14) However, carbapenems have been used more frequently in response to ever more common, highly-resistant bacteria, and carbapenem resistance is developing at an alarming rate. (15)

Carbapenem-resistant Enterobacteriaceae has demonstrated its ability to spread globally, killing patients indiscriminately from the poorest district hospitals to the richest, most advanced healthcare systems in the world. (16) Enterobacteriaceae (or "enterobacter") naturally colonize human intestines and usually are not harmful. (17) However, they are known to cause infections in the central nervous system, lower respiratory tract, bloodstream, gastrointestinal and urinary tract, and they can travel from human-to-human easily via hand carriage or through contaminated food and water. (18) In most cases, CRE infections manifest in the hospital setting, but community-acquired cases have been reported more frequently. (19) The New Delhi metallo-[beta]-lactamase-1 ("NDM-1") class of CRE is a particularly concerning global public health threat due to its presence in more than one bacterial species, including K. pneumonia (a hospital based threat) and E. coli (a community-related pathogen), (20) and its large reservoir in hospitals, the community, and the environment. (21)

Once CRE enters the bloodstream, the risk of death can exceed forty percent. (22) Survivors experience extended hospitalization, long-term disfigurement, and catastrophic disability. (23) In addition to the human toll, outbreaks of CRE and other ABR bacteria can have a substantial financial impact on healthcare systems and can significantly disrupt or shut down healthcare and long-term care facilities. (24)

Global antibiotic consumption has increased sharply in recent decades, and this trend is expected to continue with rising incomes and expanded access to healthcare. (25) All antibiotic use fuels resistance, but inappropriate use inside and outside hospitals is particularly concerning. (26) In hospitals around the world, broad-spectrum antibiotics are frequently overused. (27) Often, quick diagnostic tests are unavailable and clinicians must treat suspected bacterial infections empirically, based on their best guess (or in some cases "just to be sure"). (28) This practice can increase bacterial selection for ABR in settings where patients are most vulnerable to infection, such as long-term care facilities. (29)

Outside the hospital, physicians commonly prescribe antibiotics for influenza and other viral upper respiratory tract infections, or other non-bacterial ailments like malaria. (30) In many lower middle-income countries ("LMICs"), consumers can purchase antibiotics cheaply over the counter at a pharmacy without a prescription. (31) Often, patients fail to complete the full antibiotic course, either because they feel better, the antibiotics cause nausea or other side effects, or complete courses are unaffordable, of substandard quality, or otherwise unavailable. (32) Finally, antibiotics are used in massive quantities for agricultural purposes in many countries especially for food animal production. (33)

Despite the small number of documented CRE cases globally relative to other infectious diseases, experts are concerned that it may be a harbinger of worse to come. (34) Indeed, though CRE may be one of the most formidable threats, other resistant bacterial infections like methicillin-resistant 5. aureas (MRSA), extended-spectrum ([beta]-lactamase (ESBL)-producing enterobacter, vancomycin-resistant Enterococcus, and drug-resistant Neisseria gonorrhoeae also threaten to kill patients and burden health systems around the world. (35) Increasing international travel and trade, poor sanitation and hygiene, and the rising popularity of medical tourism are the main drivers of ABR transmission worldwide. (36) Concerted global action is urgently needed to prevent and treat these emerging infections before it is too late.

III. NEW BUSINESS MODELS ARE NEEDED FOR INNOVATION, ACCESS, AND CONSERVATION

The introduction of antibiotics in the early twentieth century was transformative. Antibiotics dramatically reduced deaths from bacterial infections and opened the door to major advancements in modern medicine. Medical procedures like lifesaving invasive surgeries, organ and bone marrow transplants, chemotherapy, knee and hip replacements, and neonatal intensive care all depend on antibiotics to make them safer. (37) As resistance develops, however, fewer and fewer drugs remain effective, changing risk/benefit calculations for physicians and their patients. (38) Most antibiotic classes in use today were introduced during the "golden age" of antibiotic discovery between the 1940s and 1980s. (39) Since then, only two novel classes of antibiotics have entered the market. (40)

The scientific, regulatory, and economic reasons for the weak antibiotic pipeline have been examined at length. In short, the expected return on investment for antibiotics is insufficient to attract pharmaceutical companies to the field. Bringing a new drug to market can take a decade or more, and companies must make substantial financial investments to overcome scientific bottlenecks and to support expensive, complicated clinical trials. (41) From a scientific perspective, most of the "low-hanging fruit" has been picked from available chemical libraries, and existing screening methods uncover fewer lead compounds, especially for the toughest-to-treat Gram-negative bacteria. (42) Moreover, lead compounds, once discovered, are often difficult to optimize for effectiveness in the human body. (43) At the same time, the declining investment in antibiotic R&D has led to a "brain drain" of investigators seeking new approaches to discovery. (44) From a regulatory perspective, the existing antibiotic review and approval framework is thought to be poorly aligned with the scientific and epidemiological realities of ABR, though the FDA and other regulatory bodies have recently made progress to clarify and streamline regulatory requirements. (45)

Finally, the commercial market for new antibiotics is characterized by uncertainty and low financial returns relative to other drugs. (46) Many antibiotics introduced in the last few decades have failed to compete with antibiotics already on the market, which tend to be cheaper and (for the most part) still effective. (47) Moreover, because new second-line antibiotics are typically reserved for use only when other antibiotics fail, companies risk small sales margins for most or all of the product's patent life. In response to these challenges, large companies have abandoned the antibiotics field in favor of more lucrative markets like cancer drugs and chronic disease treatments. (48) In recent years, the number of antibiotics in the R&D pipeline has modestly increased, with a handful of promising products advancing through clinical development. (49) However, given the high failure rate experienced during the clinical development stage it is still too soon to celebrate.

The patent system drives incentives for drug innovation by delaying generic competition, thereby allowing innovator companies to charge higher prices for the product over a specified time period. (50) Protecting intellectual property ("IP") rights assures companies and their investors that there will be commercial reward for investing in an innovator product. Expected profit therefore serves as a natural "pull" for the private sector to make the substantial R&D investments necessary to develop new pharmaceuticals, vaccines, and other biotechnology. Economic incentive policies aim to tip the balance of investment required versus expected commercial return in favor of investing in R&D. They are generally categorized as "push" or "pull" mechanisms. (51) Early incentive models were designed to correct market failures for rare diseases and infections primarily burdening the poor. (52) Over time, however, similar ideas have also been proposed to stimulate R&D for other biotechnology products facing market challenges, such as medical countermeasures ("MCMs") and new antibiotics. (53) Because push and pull incentives offer different advantages, (54) it is expected that some combination will be needed to revitalize the antibacterial pipeline. (55) Therefore, business models for antibacterial product development should have flexibility to consider a menu of economic incentive options.

A. BALANCING INNOVATION WITH ACCESS AND CONSERVATION

Economic incentive policies alone will not solve the global burden of bacterial infections. Also needed are mechanisms to ensure that new products will be available to patients who need them, as well as measures to conserve the effectiveness of both existing and new antibiotics. (56) This Part describes the tension between these three aims, which sets antibiotic innovation policy apart from the familiar global health product development paradigms.

1. Access

More people die globally from treatable bacterial infections than from resistant bacteria. (57) Childhood pneumonia, which kills nearly one million children under the age of five each year, illustrates the stark global disparity in access to first-line and second-line antibiotics. (58) Effective first-line oral antibiotics are available on the global market and can be administered by trained health workers in community settings using treatment guidelines and case management. (59) Nevertheless, limited access to facility-based care, lack of pediatric formulations, and national-level rules restricting who can administer antibiotics are just a few examples of the many factors preventing access to treatment. (60) Global access to novel antibiotics is even more limited. (61)

The tension between innovation and access is a not new to global health. The patent system favors markets willing and able to pay high prices for patent-protected drugs, often excluding from the market those poor patients and LMICs unable to afford them. (62) The challenge, therefore, is to "balance claims to [IP] rights against the rights to access to needed medicines, the common good, and the obligation to aid." (63) However, other factors also limit access to antibiotics. First, global access to pharmaceuticals requires approval by national drug regulatory authorities, which vary in terms of clinical data and quality standards. (64) Global registration of pharmaceuticals is expensive and time consuming, which further delays access to all drugs, including antibiotics. Second, even if drugs were registered and made freely available in all LMICs, access also requires that drugs are actually delivered to patients who need them. This requires infrastructure and the means to transport, distribute, and administer medications to patients. (65) Finally, counterfeit or substandard medicines circulating in the market further threaten the supply chain, harm patients, and, in the case of antimicrobials, can further drive resistance. (66) For these reasons, global health experts agree that access requires broad systems-level strengthening that extends beyond IP rights, drug regulatory authorities, and supply chain assessments. (67)

2. Conservation

Antibiotic conservation policies aim to preserve antibiotic effectiveness by restricting inappropriate antibiotic use. (68) Conservation strategies include efforts to prevent infections, such as vaccine administration, (69) hand hygiene training, and other infection control protocols. (70) In addition, antibiotic stewardship programs ("ASPs") provide structured guidance, support, and oversight to ensure responsible and appropriate selection and use of antibiotics to improve patient outcomes and monitor the emergence of resistance within hospitals and health systems. (71) ASPs often require diagnostic confirmation of bacterial infection and antibacterial susceptibility testing to ensure proper antibiotic selection. (72) Although ASPs have become more common in hospitals and nursing homes in rich countries, they are virtually non-existent in most LMICs. (73)

Governments also restrict antibiotic consumption through regulatory means. Prescription-only laws and regulations are one way to ensure that antibiotics are prescribed appropriately by a trained clinician. (74) Even though most countries have these laws on the books, they are loosely enforced in many LMICs. (75) Most antibiotics available without a prescription in LMICs are first-line oral antibiotics, but a recent report highlights an alarming increase in retail sales of carbapenems and other second line or last-resort antibiotics. (76) This raises the concern that powerful antibiotics are being used inappropriately, outside the guidance of trained medical personnel, and possibly without a prescription. (77)

Strategies to conserve antibiotic effectiveness can work against efforts to increase antibiotic access. (78) In countries with poor health delivery systems, prescription rules can limit appropriate access to antibiotics, especially in rural or other remote areas. (79) Similarly, restricting antibiotic sales or prescriptions through regulation, or simply letting market prices naturally limit sales, disproportionately favors those governments, hospitals, and patients willing and able to pay. (80) More importantly, these strategies are blunt instruments; they may reduce overall antibiotic consumption, but they will likely also reduce access to patients who actually need them. (81)

Conservation strategies can also inhibit strategies to incentivize antibiotic innovation. Under the patent system, the reward for innovation is measured by sales; the more antibiotics sold, the more profit. Strategies to limit antibiotic sales and prescriptions can, therefore, undermine economic incentive policies for innovation (and vice versa). To fix this problem, some have proposed bold policy changes to decouple, or "de-link," antibiotics sales volume from financial reward. (82) These models would represent a dramatic departure from the traditional patent system and many experts have agreed that such a paradigm shift may be needed. (83)

B. LOOKING BEYOND ANTIBIOTICS

The challenges facing antibiotic development highlight the need for innovative business models. Moreover, the tension inherent in balancing the values of innovation, access, and conservation reinforces the need to consider other technologies to prevent, diagnose, and treat bacterial infections. Alternatives include vaccines, monoclonal antibodies, antimicrobial peptides ("AMP"), phage therapies, and faster, cheaper diagnostics. (84) Importantly, these alternative technologies can reduce antibiotic consumption, thereby preserving the effectiveness of new and existing antibiotics. Like antibiotics, however, these technologies face their own barriers to development and are unlikely to replace traditional antibiotics in the short term. (85) New business models for ABR must, therefore, be designed to adapt to different scientific, regulatory, and economic barriers depending on the technology pursued. …

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