The Role of Pharmaceutical Companies in Global Health: Lessons from Bedaquiline

The Role of Pharmaceutical Companies in Global Health: Lessons From Bedaquiline

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THE ROLE OF PHARMACEUTICAL COMPANIES IN GLOBAL HEALTH: LESSONS

FROM BEDAQUILINE

TIFFANY CHAN

A DELTA Doctoral Thesis Submitted to the Faculty of

The Harvard T.H. Chan School of Public Health

In Partial Fulfillment of the Requirements

for the Degree of Doctor of Public Health

Harvard University

Boston, Massachusetts.

May, 2018

Dissertation Advisor: Nancy Turnbull Tiffany Chan

The Role of Pharmaceutical Companies in Global Health: Lessons from Bedaquiline

Abstract

Many diseases that cause significant morbidity and mortality around the world do not attract adequate investment from private sector pharmaceutical companies to research and develop new medicines. During an eight-month fellowship with the Johnson & Johnson Global Public Health team, I explored the role of pharmaceutical companies in tackling global health problems. I use a case study on bedaquiline (brand name SIRTURO®), the first new drug with a novel mechanism of action used to treat tuberculosis in 50 years, to explore barriers and facilitators to engaging pharmaceutical companies in tackling complex global health problems. Further, I discuss implications and lessons from the development of bedaquiline, and the motivations of the pharmaceutical company behind it, that the public health community can learn about the role of pharmaceutical companies in global health.

Table of Contents

Abstract ...... ii List of Figures with Captions ...... v Acknowledgements ...... vi Part I: Introduction to Market Failure in the Development of Drugs for Neglected Diseases ...... 1 Methods ...... 5 Part II: Understanding the Context of TB ...... 6 TB Control Efforts Focus on Biomedical Interventions, Elevating the Role of Pharmaceuticals ...... 9 Pharmacological Management of TB Treatment ...... 14 Part III: Incentives for Pharmaceutical Engagement ...... 26 Overview of the Pharmaceutical Industry ...... 27 Misaligned Incentives Deter Pharmaceutical Companies from Investing in TB Research & Development ...... 31 Creating a Reason to Develop New Drugs for TB ...... 35 Push Incentives: Lowering Risk ...... 36 Process Incentives: Increasing Institutional Capacity ...... 37 Pull Incentives: Attracting Investment ...... 40 Nonfinancial Reasons for Pharmaceutical Companies to Invest in TB ...... 41 Part IV: A Bright Spot for TB Drug Development – J&J’s Development of Bedaquiline ...... 46 Background on Johnson & Johnson ...... 48 Case Study: Developing Bedaquiline ...... 49 Creation of a Global Public Health Organization ...... 63 Three Strategic Challenges to Making Bedaquiline Accessible ...... 68 Improving Adoption despite Knowledge Gaps ...... 69 Balancing Availability with Stewardship ...... 74 Managing Affordability alongside GPH Self-sustainability ...... 80 South Africa: An Example of Bedaquiline Access ...... 86 Part V: Discussion on Lessons from the Bedaquiline Case ...... 90 Bibliography ...... 109

iii

List of Figures with Captions

Figure 1. Terminology for Drug-resistant TB

Figure 2. Estimated Prices of WHO-recommended Drug Regimens

Acknowledgements

This DELTA would not have been possible without the incredible researchers, practitioners, and community members involved in tuberculosis control efforts around the world and concerned about development of new technologies for the prevention, control, and treatment on tuberculosis. I got a glimpse into the tuberculosis community and various organizations’ and individuals’ contributions and dedication to eradicating the disease, a prime example of one of the wicked problems we face as a global community. In particular, support and open doors from

Johnson & Johnson’s Global Public Health team, the Stop TB Partnership, and other global health institutions and industry fora, allowed me to develop new perspectives on these challenging and complex issues.

Many thanks to my committee members Nancy Turnbull, Linda Cyr, and Jesse Bump for supporting my intellectual, professional, and personal growth, asking critical questions, and providing feedback and guidance through this process. Your encouragement to focus on my personal leadership journey gave me freedom to explore new topics and come away from this experience with new insights and approaches to learning that have shifted my paradigm on achievement. My deepest gratitude to the many faculty members at the Harvard T.H. Chan

School of Public Health who have helped shape my thinking and personal reflection throughout this DELTA and the broader DrPH program, particularly Michael McCormack and Fawn Phelps.

The past three years, I have had the privilege and pleasure of working with many professors, staff members, and colleagues at the Harvard T.H. Chan School of Public Health and across the broader university system. To the teams and varied organizations I have learned from and worked with over the past three years – the Massachusetts Department of Public Health

(Boston, Massachusetts), World Health Partners (New Delhi, India), YLabs (Kigali, Rwanda),

Mount Auburn Hospital (Cambridge, Massachusetts, USA), the Harvard Innovation Lab

(Boston, Massachusetts), and the Harvard Public Opinion Research Group – and the DrPH program that has made many of these opportunities possible, I am grateful.

My cherished alma mater, Wellesley College, formed the foundation of my intellectual curiosity, and its mission – Non Ministrari sed Ministrare – continues to inspire me to look beyond myself toward the larger world around me. The relationships, ideas, and drive forged in that community, continue to sustain me today.

I could not have done this without the support of my family and friends. My DrPH cohort, in particular, has been a source of wisdom, inspiration, and friendship, particularly my peer mentors – Vanessa, Chris, and Lavinia – and the group we have created (“Tim”) to house our continued coaching relationship, and study partners (“Library Ladies”). I cherish the relationships I have developed with my colleagues and friends who have been through this journey with me and whose personal narratives serve as examples. I am honored to be in their company and look forward to working together beyond the program.

Thank you to my grandparents who gave me roots in the United States and imbued my family with values of honesty, generosity, and learning that I strive to live every day. To my parents, Chris and Shirley, who gave me both the privilege and values that allowed and encouraged me to continue to learn and seek a higher education, and whose unconditional love and wise counsel serves as a bedrock for my growth. Thank you to my sisters and best friends,

Vivian and Karina, for keeping me grounded, cheering me up when I’m down, and sending me support and real-talk all the way from California. And last but not least, for reading every draft, helping me prepare for my presentation, keeping me grounded, courageous, and hopeful through tough times, and holding my hand throughout this three-year journey, thank you, Shashank.

vii

Part I: Introduction to Market Failure in the Development of Drugs for Neglected Diseases

Neglected diseases disproportionately affect the world’s poorest populations. Since 2005, the term neglected tropical diseases (NTDs) has been narrowly defined by researchers and the

World Health Organization as a set of diseases that collectively affect over a billion people but have historically received little attention. NTDs do not include HIV, malaria, and tuberculosis

(TB), which also primarily affect low-income people and parts of the world but are known as

“The Big Three” infectious diseases for receiving outsized global attention, mobilization, and funding over the past two decades. Still, these diseases are similar to NTDs in their overwhelming concentration in low- and middle-income countries with limited health budgets, and poor and marginalized populations with limited purchasing power. In particular, malaria and tuberculosis, which unlike HIV which has a significant presence in higher-income countries, are sometimes grouped with WHO-defined NTDs and other diseases of poverty as “neglected diseases” (Pedrique et al., 2013). While these diseases continue to cause significant mortality, morbidity, and poverty, they fail to attract proportionate or sufficient investment in research and development based on the traditional economics of drug development.

The high cost of drug research and development (R&D) motivates private, for-profit pharmaceutical companies to invest in profitable drugs. These costs are rising, driven by factors such as increasingly stringent national regulatory requirements on safety and efficacy of new drugs and the high risk of failure after lengthy development processes. As a result, companies seeking to generate profits concentrate on the medical needs of populations that are able and willing to pay high prices for new medicines. In contrast, lower incomes characteristic of populations affected by NTDs, malaria, and TB are associated with smaller market sizes, which empirical research demonstrates to be a driver of pharmaceutical innovation (Acemoglu & Linn,

2004). Further, most private, for-profit companies have a fiduciary responsibility to their shareholders to maximize profit. Since such companies account for a large share of global drug development spending and possess expertise in developing new drugs, which means that under free market conditions, it is unlikely that they would invest in R&D for medicines to treat diseases with small or nonexistent markets. The uneven distribution of R&D expenditures across diseases suggests a market failure exists in the pharmaceutical market for infectious diseases that are highly prevalent in lower income countries. In 2002, Trouiller et al. published a groundbreaking and frequently cited finding that highlights this market failure: from 1975 to

1999, far less than 1 percent (16/1,393) of new chemical entities targeted these diseases, even though in 1999, they accounted for over 10% of the global disease burden. There was a 13-fold greater chance of a drug being brought to market for central-nervous-system disorders or cancer

(Trouiller et al., 2002), underscoring the stark imbalance between R&D allocation and global health needs. In economic terms, leaving allocation of resources for R&D to the market results in a decision rule for R&D investment to maximize profit, rather than health outcomes (Sloan &

Hsieh, 2007). Further, in some cases incomes of affected populations may be so low that effective demand for disease prevention and therapy is also low, requiring other interventions, particularly sources of financial assistance, from governments or foundations (Sloan & Hsieh,

2007). These market failures have led to what Reich (2000) termed a “global drug gap” in which the private sector invests almost exclusively in drugs for the developed world that will be marketable and profitable.

For many of these infectious diseases, availability of curative drugs could greatly reduce morbidity and mortality. Acknowledging this, since 1999, funding and novel partnerships across the public and private sectors have greatly increased to support the development of drugs for

2 diseases that primarily affect lower-income countries, particularly HIV/AIDS, malaria, and TB.

Renewed interest in developing drugs for neglected diseases marks a major shift from previous decades when diseases affecting poor people in poor places were largely overlooked by the pharmaceutical industry. In 2009, an updated count of new chemical entities developed for neglected diseases revealed 26 had been developed since 2000, suggesting that improvement has been made in the development of new drugs (Cohen et al., 2010). New relationships between public funders, non-profit organizations, and pharmaceutical companies to pool and channel public funds toward the development of new products to prevent and treat these diseases (Moran,

2005) have expanded institutional capacity to overcome the aforementioned market failures. The percentage of approved neglected disease products sponsored by the private pharmaceutical industry almost halved (83% to 46%), while the percentage sponsored by public-private partnerships increased threefold (from 15% to 46%) (Cohen et al., 2010), suggesting an increased role of these novel collaborations and a shift away from independent pharmaceutical company development.

However, progress has been uneven across diseases. For example, malaria has seen a

250% increase in numbers of new products from 2000-2009, compared to the 1975–1999 period; while tuberculosis has received similar funding, no new TB drug was approved in the same time and the pipeline was smaller (Cohen et al., 2010). The lack of advancement and investment in new drugs for TB is curious given its prevalence and assumed advantage given its grouping as a

“Big Three” disease. A recent uptick in activity around new drug development for tuberculosis in

2012, for the first time in 50 years, invites inquiry into the barriers and facilitators that enabled such a shift.

Indeed, while TB is often called a disease of antiquity, “an ancient scourge” (Daniels,

2006), and “one of the most ancient diseases of mankind” (Gupta et al., 2011), these epithets obscure the reality that tuberculosis is the top infectious disease killer today. The disproportionate recognition of TB’s global burden, and the rising threat of drug-resistant TB strains, is reflected in investment in TB R&D. Though TB accounts for nearly 2% of disability- adjusted life-years (DALYs) and 2% of deaths globally, it only receives 0.25% of estimated $265 billion spent on medical research each year (WHO, 2017). Compared to HIV and malaria, TB research receives less total funding, and less funding relative to its share of morbidity and premature mortality (WHO, 2017). Further, annual funding for R&D in TB has declined since

2009 when accounting for inflation, driven by declining investments from the pharmaceutical industry and stagnating spending from major public and philanthropic funding sources (WHO,

2017).

Janssen Pharmaceutica, the pharmaceutical subsidiary of Johnson & Johnson (J&J), faces the same profit-driven pressures as other for-profit, pharmaceutical companies. Like most pharmaceutical companies, through the 1990s, Janssen had a limited R&D pipeline addressing developing countries. However, a team of dedicated scientists successfully discovered a compound that was very effective in stopping TB, and knew they had stumbled upon a breakthrough. They nurtured this drug despite scientific challenges and ultimately identified a novel mechanism of action against the bacteria, which would become the first new drug for tuberculosis in 50 years.

Investing in TB was not a conventional decision for the company. However, a mix of financial subsidies and incentives available for the development of neglected diseases like TB facilitated J&J’s decisions to bring bedaquiline to market. By the time bedaquiline reached its

4 later stages of development, J&J was able to develop strategic partnerships with new public sector and non-profit institutions, such the US Agency for International Development’s TB program and public-private partnerships focused on creating novel tuberculosis treatments.

The narrative arc of bedaquiline also follows challenges in creating access to the new technology, managing the tension between availability and stewardship of new antibiotics, decision-making in the face of clinical uncertainty and knowledge gaps, and balancing drug affordability and financial viability of J&J’s internal global public health organization. In the process, the company has encountered and pivoted in the context of a long-standing, centralized global TB control program, shortfalls of weak health systems, and controversies around relying on large pharmaceutical companies to innovate and provide access to essential medicines.

In recounting the story of bedaquiline, this paper will seek to address two key questions.

One, prior to bedaquiline, why were no new medicines developed for TB developed for 40 years? Perhaps more importantly, what can the public health community learn about pharmaceutical companies’ considerations and approaches to R&D and dissemination of drugs for neglected diseases?

Methods

From July 2017 until March 2018, I joined Johnson & Johnson’s Global Public Health team as a Research & Policy Fellow. I worked with J&J’s Senior Director of Global Health

Systems Policy and Partnerships, whose responsibilities include the establishment of novel collaborations with governments, multilaterals, and civil society around shared priorities in global public health. I also worked closely with the Vice President, Global Head of Tuberculosis to support the development of the Private Sector Constituency of the Stop TB Partnership. In this role, I participated in internal discussions about the policy priorities of the Global Public Health

5 team, planning meetings for the UN High-Level Meeting on Tuberculosis in 2018, and engagements with partners like Global Citizen, Global Fund Private Sector Delegation, and the

International Federation of Pharmaceutical Manufacturers & Associations.

As a participant observer, I used a blend of observation, formal and informal interviews, and document analysis to collect information. The case study on bedaquiline also draws fromprimary and secondary research, coupled with first-hand interviews with unnamed members of J&J’s Global Public Health team, who are and were charged with the oversight of bedaquiline’s development and access strategy.

This paper will begin with a description of the condition of tuberculosis and a brief history of the social response to this disease to set the context for J&J’s entry into this disease area. Next, the paper will explore the role of pharmaceutical interventions in tuberculosis control, particularly the emergence of biomedicine as the dominant approach for TB control and the rise of drug resistance. This is followed by an analysis of incentives for pharmaceutical companies to engage in tuberculosis R&D. The paper will then take a close look at J&J’s experience with bedaquiline, and challenges in increasing access to the drug. Lastly, the paper will provide insights on the financial and strategic impact of bedaquiline on J&J, lessons for public-pharma partnerships in TB, and pharma’s role across the broader global health landscape.

Part II: Understanding the Context of TB

Tuberculosis (TB) is an airborne infectious disease that has been a leading cause of death for centuries. Despite the existence of a curative treatment regimen since the mid-20th century,

TB has eluded disease control efforts. In fact, after the discovery of effective medicines to treat

TB over 50 years ago, the global health community believed that the disease would soon be eradicated. This was not to be, and the rise of HIV, which created a new population that was

6 highly vulnerable to TB, and drug-resistant strains of TB in the following decades led the WHO to declare TB to be a global health emergency in 1993. This declaration galvanized new momentum to control TB, which has been strengthened by the development of new public- private initiatives to increase political will and funding to tackle TB. However, despite wide recognition that new tools are needed to prevent, diagnose, and treat TB, particularly growing drug resistance, TB remains a highly unattractive investment opportunity for private, for-profit pharmaceutical companies.

Identifying the Disease

Tuberculosis has been observed in humans from ancient times, but scientific and medical advances in the mid-19th century brought a new understanding of the biological determinants of diseases, including TB. The biggest breakthrough came on March 24, 1882, when Hermann

Heinrich Robert Koch famously isolated Mycobacterium tuberculosis, the causative agent of tuberculosis. Though TB is rarely found in Western countries today, in the 1800s TB was estimated to cause the deaths of one if four adults in Europe and North America (Daniels, 2006).

Building upon previous studies of tuberculosis, particularly the demonstration by Jean-Antoine

Villemin that TB was an infectious disease, and using innovative techniques – a novel staining procedure that could penetrate the bacteria’s hardy cell wall and serum-based culture to reproduce the disease (Cambau & Drancourt, 2014), Koch’s discovery marked a new era of microbiology and scientific understanding of TB. Over the fifty years, a partially effective vaccine (i.e. Bacillus Calmette-Guerin vaccine), basic diagnostics (i.e. the tuberculin skin test), and the first curative treatment for TB, streptomycin, would be discovered, transforming options for TB patients.

The decline in TB rates in richer countries due to rising living standards as a result of higher incomes, improved public health measures for sanitation and hygiene, and the success of the new chemotherapy option in curing TB, generated a misconception in the late 1960s and 70s that the disease had been conquered. As a result, no new drugs were developed for years, and isoniazid (1952), pyrazanimide (1954), ethambutol (1962), and rifampicin (1963) continue to comprise the core four-drug, six to nine-month regimen to treat tuberculosis today (WHO

Treatment Guidelines, 2016). Further, the shift of tuberculosis care to the lower-cost outpatient setting and waves of budget cuts to the public health system in the 1970s and 80s severely reduced needed resources to maintain surveillance, prevention, and treatment activities. At the global level, global health institutions and academicians in developed countries seemed to have lost interest in tuberculosis. In the scientific community, TB-focused journals transformed into respiratory disease journals and, in 1985, the British Medical Research Council Tuberculosis

Units, which had played a key role in development and testing of modern control efforts, closed

(Raviglione & Pio, 2002). Further, the WHO Director-General began to group TB activities under other bacterial disease programs in its annual report to the World Health Assembly; by

1978, the WHO Tuberculosis Unit had integrated other diseases of the respiratory system and became the “Tuberculosis and Respiratory Infections Unit” without an increase in resources to accommodate the expanded mandate (Raviglione & Pio, 2002).

During this time, though TB appeared to be declining in high-income countries, the disease was never actually eradicated. As TB hospitals and chest clinics closed and governments around the world did little to cultivate research and expertise to respond to TB, the disease was relegated to poor urban areas in rich countries and allowed to propagate in developing countries

(Specter, 1992; Garrett, 2000). The deprioritization of TB at the global health level meant that by

1989, only two professionals in the WHO Headquarters were dedicated to TB, and when the

HIV/AIDS pandemic began to spread and the fall of the Soviet Union led to a crisis in drug resistance (Garrett, 2000), the world lacked visibility and expertise into effective tuberculosis control (Raviglione & Pio, 2002).

TB Control Efforts Focus on Biomedical Interventions, Elevating the Role of Pharmaceuticals

Since Koch discovered Mycobacterium tuberculosis in 1882, biomedical individualism has served as the dominant frame for infectious disease control efforts. The biomedical model emphasizes biological determinants of disease amenable to intervention through the health care system, considers social determinants of disease to be secondary, and sees populations and population patters as a sum reflection of individual cases (Krieger, 2000). Despite research and acknowledgment of the multifactorial etiology of tuberculosis - considering host, agent, and environmental factors - the disease in populations has therefore been reduced to a question of disease in individuals, and medical interventions as the primary mechanisms of control (Krieger,

2000).

Interrupting transmission through rapid initiation of a standardized, four-drug six-month medication treatment is the primary strategy that WHO has espoused since the 1990s. Since tuberculosis disease most often manifests as pulmonary tuberculosis, in which the bacteria infects the lungs and is transmitted through the respiratory system, it is an airborne, and therefore easily spreadable disease. With pulmonary tuberculosis, the infection spreads through the air from individuals with tuberculosis who cough, sneeze, or talk, spreading airborne droplets containing tuberculosis that others inhale by breathing. The process by which tuberculosis is transmitted can be summarized by the following cascade: (1) a source case of tuberculosis (2) generates infectious particles that (3) survive in the air and (4) are inhaled by a susceptible

9 individual (5) who may become infected and (6) then has the potential to develop tuberculosis disease (Churchyard et al., 2017). Typically, repeated and extended exposure is required for tuberculosis to be transmitted, and to reduce incidence, interventions to interrupt tuberculosis transmission, particularly among targeted high-risk groups and settings are a major focus of tuberculosis control (Churchyard et al., 2017). However, there are significant barriers to patients receiving timely diagnosis, appropriate treatment, and improved outcomes.

Barriers to TB treatment and control in high-burden countries

For the past several decades, WHO’s primary strategy has been “passive” case finding, which involved waiting until ill patients present themselves at health facilities. However, over

40% of the 10.4 million people who get sick with TB do not receive care, and are “missed” by health systems after they are not diagnosed, treated, or reported (Global Fund, 2017). Many barriers exist at the patient and system levels that prevent patients from actively seeking care at facilities, receiving timely and accurate diagnosis, and initiating and adhering to proper treatment. For example, at the patient-level, perception of the disease, stigma, knowledge about

TB and symptoms, delayed care-seeking and treatment initiation, and poor adherence all contribute to poor outcomes; at the health-system level, barriers include availability and accessibility of quality health care services, limited infrastructure or resources (e.g. geography or distance to TB treatment centers, availability of laboratory tests and drugs), and direct, indirect, system, and caregiver costs (Sullivan et al., 2017). Recent focus on solving this treatment and care gap, such as a $190 million initiative by the Global Fund for AIDS, TB, and Malaria, have aimed to target these “missing” cases (Global Fund, 2017), but much more work needs to be done to actively screen at-risk populations and address barriers to accessing TB services.

A particular challenge of TB is the potential lack, delay, or temporary onset of active disease. WHO often states that an estimated one out of every three people on earth has an asymptomatic, “latent” infection of Mycobacterium tuberculosis. The traditional concept of latency posited a “latent TB” vs. “active disease” binary, in which healthy people’s immune systems “wall off” the bacteria, isolating it from impacting the body while the bacteria goes into hibernation. Indeed, in most healthy people, TB infection causes no symptoms. More recent evidence suggests that the process is more nuanced: low numbers of bacteria present during latent tuberculosis infection result from a dynamic equilibrium of host-pathogen interactions better characterized as a continuum of host-pathogen activity (Salgame, 2015). Individuals can completely clear the infection, have asymptomatic granulomas (collections of macrophages and other immune cells), switch between active and latent disease, or have full-fledged pulmonary

TB. However, scientific understanding of TB has not yet advanced to be able to identifying people who are at risk of reactivating tuberculosis. While the science is well-established that progression to disease can be triggered by a compromised immune system, as with HIV/AIDS, or by other risk factors mentioned earlier, there is limited understanding of biomarkers that indicate likelihood of progression of the disease within individuals. As a result, additional research needs to be conducted to better target preventive and proactive treatment measures.

Rapid diagnostics are important for detecting patients earlier in disease progression to initiate treatment in a timely manner, isolate active TB patients to reduce transmission, and identify high-risk individuals who have had contact with TB patients. Diagnosing drug-resistant

TB is even more challenging: it requires human and laboratory capacity for drug-sensitivity testing and analysis, and tracking 9 to 24 months of daily drug treatment (Nathanson et al., 2010;

Shin et al., 2008). Technical and health systems challenges contribute to low levels of case

11 detection and initiation of treatment. From a scientific standpoint, one of the greatest challenges in TB detection begins with its unusual biology. All species of bacteria in the Mycobacterium complex are distinguished by an unusual, “waxy” coating on its cell wall, contributing to the bacteria’s natural resistance to many antibiotics and making Mycobacterial infections

“notoriously” difficult to detect and treat (Sacks & Behrman, 2009).

The most common diagnostic test is a sputum-based microscopy test, in which lab technicians or healthcare providers grow a clinical specimen and count numbers of acid-fast stained bacilli using a microscope, the same technique that Koch used to identify the tuberculosis bacillus in 1882. Because Mycobacterium tuberculosis are extraordinarily slow-growing bacilli, it takes three to six weeks to grow the bacteria in a culture in a laboratory, and an additional three to six weeks to screen for antibiotic resistance (Sacks & Behrman, 2009). As a result, diagnosis using this test typically requires extended laboratory procedures, which can lead to delayed diagnosis, ineffective treatment, and greater risks of transmission. Further, this method only diagnoses about half of all TB cases in adults (Frieden, 2004), and even fewer in children (Detjen et al., 2015) and HIV-positive individuals (Harries, 1997). However, despite its drawbacks,

WHO recommends use of sputum-based microscopy as part of the TB standard of care.

Other commonly used diagnostic tools also originated at the turn of the 20th century: tuberculin skin tests, also known as intradermal Mantoux tests, were the first widely used TB tests in 1910 and chest X-rays were used for mass radiography campaigns until the 1950s. While these continue to be functional tools, with the latter included in the latest WHO recommendations for TB control, the first requires availability of X-rays and training in radiography to interpret results, while the second has a 48-72 hour delay, lacks specificity, and

12 can also be misread. The use of century-old and insufficient tools highlights the great need for both faster, more sensitive, and more specific diagnostic tests for TB.

Over the past decade, several promising new tools for diagnosing tuberculosis more quickly and effectively have emerged, though adoption has been slow. Most notably, the Gene

Xpert MTB/RIF (Cepheid, Sunnyvale, California) machine was introduced in 2010. Xpert can provide rapid and sensitive detection of TB and rifampicin resistance in less than two hours, solving a real need for resistance detection: an estimated 450,000 people who developed MDR-

TB in 2012, only 94,000 were detected (20.9%) and only 77,000 (17.1%) were started on second-line treatment (WHO, 2013; Bloom, et al., 2017). However, Xpert is expensive, costing

$17,000 per unit and $10 per tests, and given the expense and sophistication is suited for hospital and major laboratories rather than at the point-of-care (Bloom et al., 2017). In fact, the majority of Xpert cartridges are issued to only one country, South Africa (Pai & Schilt, 2015), demonstrating slow and limited uptake since 2010. A new test, Omni, which is battery-operated and designed for ambulatory settings, holds some promise for improving testing (WHO, 2017), but roll-out remains to be seen.

As a result of diagnostic challenges, from the fundamental challenges of the bacteria itself to the struggle to develop and disseminate new tools to more quickly and accurately detect the disease, the number of patients with tuberculosis, particularly those with varying levels of drug resistance, is likely an underestimate. For pharmaceutical companies attempting to size the market for TB, not to mention drug-resistant TB, in high-burden countries, the numbers are often based on country-level estimates that may not translate into real patients who can receive care.

Pharmacological Management of TB Treatment

The development of chemotherapy options to cure TB in the 1940s heralded a new age for TB control, and soon after, TB control efforts became oriented around the delivery of treatment to patients with TB disease.

A Legacy of National TB Programme Infrastructure Oriented Around Drug Delivery

The highly centralized, WHO-led model of TB care seen today has its vestiges in the initial programmatic model developed to conduct mass screenings of populations for TB and deliver these new TB drugs. In the 1940s and 50s, the discovery of effective chemotherapeutic agents against many infectious diseases, including TB, prompted the WHO to establish country- level vertical control programs, independent of the general health infrastructure and other vertical programs (Raviglione & Pio, 2002). From 1948 to 1963, a vertical managerial policy for tuberculosis control was seen as “necessary” because the experimental chemotherapy treatment methods requiring specialized services for delivery (Raviglione & Pio, 2002). These programs were staffed with specialized personnel at every level, with its own officers for training, supervision, logistics, and health education, as well as separate laboratory services (Raviglione &

Pio, 2002). In most countries, the managerial autonomy of these specially funded programs and independence from the broader health system has persisted, despite waves of health system reform and phases of health service integration with general health care services over the next couple of decades. Today, almost every country has a dedicated TB unit or National TB

Programme, for which directives and regulations are developed by WHO’s Global TB

Programme and cascaded down to the country and local levels through these dedicated TB programs.

In 1993 the WHO declared that TB was a global health emergency and launched a package of measures for TB diagnosis and treatment known as the Directly Observed Therapy,

Short course (DOTS) strategy (WHO, 1994; UN General Assembly 2000). A detailed study of the policy formation and transfer of DOTS (Ogden et al., 2003) suggests that WHO Global TB

Programme took a strongly political approach to what is usually thought of as a technical health policy process, using an important window of opportunity opened by the global HIV/AIDS problem and an alarming MDR-TB outbreak in New York to develop a simple, branded solution by which to solve it. This approach, which recombined old strategies for detecting and treating

TB, unified and simplified at least five recommended regimens for treatment (Murray, Styblo, and Rouillon, 1990), though in practice the existing variance in drug combinations used around the world was likely much greater. DOTS was built around the concept of directly observing patients as they consumed their TB medications to monitor and enforce adherence, and was branded and promoted as a best-practice strategy applicable to all countries, supported by evidence of its cost-effectiveness (McKee et al., 2006). The WHO Directly-Observed Treatment

– Short-Course (DOTS) included a five-point strategy: sustained political and financial commitment, diagnosis by quality ensured sputum-smear microscopy, standardized short-course anti-TB treatment given under direct and supportive observation (DOT), regular, uninterrupted supply of high quality anti-TB drugs, and standardized recording and reporting.

Even after the standardized DOTS regimen was consolidated and promoted by the WHO, it was not universally adopted, or effective, in many places. In the 1990s, WHO insisted that governments should adopt the DOTS therapy approach to TB control, but most developing countries lacked a public health infrastructure that could effectively distribute recommended drugs to their poorest citizens. The WHO raised significant opposition from academics and

15 others who contested the over-simplified messaging and policy pronouncement, prioritization of operational programs over research, and top-down imposition of a “one-size fits all” approach by international institutions with little nuance or flexibility for local contexts (Ogden et al., 2003).

Keshavjee and Farmer (2012) describe DOTS as “an approach that conformed to the selective primary health care agenda: simple to treat, algorithmic, and requiring no expensive inputs”, which focused on cost-effectiveness of health interventions to the neglect of facility-based infection control, TB control and treatment of children, people with drug-resistant strains, and people with HIV-TB coinfection. Though a necessary step, standardization of DOTS was promoted as a “one size fits all” and implemented in a dogmatic manner, restricting providers from tailoring care to individual patients, particularly for patients with drug-resistant TB, and led to different policies for treating drug-resistant TB in high-income countries and low-income settings that solely relied upon DOTS (Keshavjee & Farmer, 2012). WHO has defended the exclusion of treatment of drug-resistant TB, supposedly driven by lack of laboratory infrastructure to test for drug susceptibility, lack of availability of second-line drugs in many developing country settings, and lack of understanding of the scale of drug resistance (Marais &

Zumla, 2012); treatment regimens for drug-resistant TB were later included in WHO recommendations and strategies, but treatment of drug-resistant TB continues to lag. Further, the predominance of private providers in many high-burden meant that the public sector-driven treatment and control efforts do not touch a majority of patients without concerted efforts to integrate private providers. In some places, DOTS did not work, even where authorities followed

WHO’s protocols, and drug resistance continued to climb (Garrett, 2000).

The End TB Strategy issued by WHO in 2015 has been praised by WHO’s critics for being the most comprehensive TB control strategy thus far (Bloom et al., 2017), and the most

16 ambitious given its stated goal to eliminate – rather than merely control – TB as a global health epidemic by 2035. However, disagreements over the dominant, simplified, and treatment- focused solution recommended by WHO – DOTS with some modifications – still linger. As a result, those who have advocated for more comprehensive and flexible responses, most notably several outspoken academics and civil society groups such as the Treatment Action Group and

Partners in Health, have led to long-standing policy disagreements and political fractures in the global TB community.

The Growing Threat of Drug Resistance

Antibiotic resistance to anti-TB drugs has been observed since Andrew Waksman and his team discovered the first chemotherapy to treat TB, streptomycin, in 1943 (Jones et al., 1944).

Soon after its introduction, patients who had made progress under the treatment relapsed, indicating that M. tuberculosis had developed resistance. In 1952, researchers discovered another drug that worked to inhibit the growth of Mycobacterium tuberculosis, isoniazid (Daniels, 2006).

When used together with streptomycin, isoniazid reduced rates of drug-induced resistance, demonstrating one of the principles, and complications, of TB treatment: the importance of using combinations of multiple therapies to prevent development of resistance and ensure long-lasting cures (Crofton, 1959; Fox, 1981). In the 1960s, additions of ethambutol, pyrazinamide, and rifampin, primarily based on expert opinion, successfully led to more reliable cures with shorter durations of therapy. However, until DOTS, there was no standardized use of the drugs, which were used in many permutations around the world according to expert opinion and local availability.

There are two main reasons why drug resistance to TB emerges and spreads: mismanagement of tuberculosis treatment and transmission of drug-resistant strains. The MDR-

TB epidemic has been described as an “iatrogenic” problem (Kant, 2010) - that is, caused by mistreatment or an error in health care treatment. Tuberculosis treatment is “mismanaged” when anti-tuberculosis drugs are inappropriately or incorrectly used, ineffective formulations of drugs are used, such as single drugs in “monotherapies”, poor or degraded formula quality, or prematurely terminated treatments (WHO, 2018).

TB with resistance to at least both isoniazid (INH) and rifampicin (RIF), first-line treatment drugs, is called multidrug resistant TB (MDR-TB). The two most important “classes” of second-line TB drugs to be used in such cases are injectable drugs and fluoroquinolones.

Apart from these agents, a number of miscellaneous drugs are used in addition, as part of combination therapy. The effectiveness of these latter miscellaneous drugs is generally lower, the tolerability is problematic and established breakpoints for resistance determination are lacking.

The term pre-XDR (pre-extensively drug resistant) TB is used when there is resistance to one of the two main second-line class agents (injectables or fluoroquinolones), and XDR-TB when resistance is present to both INH and RIF, injectables, and fluoroquinolones.

Figure 1. Terminology for Drug-resistant TB

 Drug-sensitive: No resistance to isoniazid or rifampicin, the two most important first-line

antibiotics used in TB treatment

 Multi-drug resistant TB (MDR-TB): Resistance to both isoniazid or rifampicin

 Pre-extremely drug resistant TB (pre-XDR TB): Resistance to both isoniazid and

rifampin, plus any fluoroquinolone and at least one of three injectable second-line drugs

(i.e., amikacin, kanamycin, or capreomycin)

Figure 1. Terminology for Drug-resistant TB (Continued)

 Extensively drug resistant TB (XDR-TB): Resistance to isoniazid, rifampicin,

fluoroquinolones, and second-line injectable drugs (i.e., amikacin, kanamycin,

capreomycin)

Public health experts have decried the lack of investment in infrastructure for contributing to the rise of drug-resistant tuberculosis. The United States provides an instructive lesson for developed countries on how gaps in the health system can lead to the emergence of more virulent strains of “old” diseases. Even when federal policy experts believed that TB was on its way to elimination, the disease remained, concentrated among poor people living in poor places. The onset of the HIV/AIDS epidemic coincided with rising homelessness, drug use, immigration from countries with high TB burdens, and other facilitators, incidence of TB, particularly drug-resistant strains, rose to epidemic proportions (Specter, 1992). As journalist

Michael Specter wrote in the New York Times, the United States had “stumbled into its first preventable epidemic, a wave of tuberculosis with strains so virulent they threaten to return pockets of American society to a time when antibiotics were unknown” (1992).

As with many other public health problems, inducing action and investment for prevention is much more difficult than conjuring up resources to respond to a crisis. The lack of proactive action to eliminate tuberculosis control in the 1980s, when the possibility was possibly within grasp and before the emergence of drug resistance, has been costly. For example, in 1987, the chief of the US Centers for Disease Control (CDC) had estimated that it would cost $36 million each year to wipe out TB in the US by 2010 (Specter, 1992). By 1992, TB had become more widespread and resistant to available therapies, and the CDC’s national proposal called for

19 fifteen times more funding ($540 million per year) to manage the epidemic (Specter, 1992).

Complacency and neglect of TB led to what many experts have called a “missed opportunity” to eliminate TB in the United States, and fostered the emergence and spread of drug-resistant TB.

In most places where drug resistance tends to spread, health systems are often ill- equipped to manage the disease. As a result, drug resistance is underdiagnosed, poorly treated, if at all, and a major driver of TB-related deaths: in 2016, 240,000 people died from drug-resistant

TB (WHO Global TB Report, 2017). Cure rates in MDR-TB are much lower than those seen in drug-sensitive TB, even though far more medicines are required for a lengthier treatment duration. Hence, MDR-TB is associated with a high mortality and is considered an important major threat to public health. Globally, only one in five people with drug-resistant TB (129,689 patients globally) started second-line MDR-TB treatment in 2016, and the average success rate was only 54% (WHO TB Report, 2017). Poor management of MDR-TB has, in turn, led to the emergence of extensively drug-resistant tuberculosis (XDR-TB), bacterial strains that are also resistant to second-line TB drugs, around the world. By the end of 2016, XDR-TB had been reported by 123 WHO Member States. In many places, XDR-TB is functionally a death sentence; even if treatment is available, there is only a 30% treatment success rate (2014 cohort)

(WHO TB Report, 2017).

From a systems perspective, MDR-TB treatment has significant influence on other parts of the health system. The complicated regimen presents major challenges from a health care workforce training, supply chain and procurement, and clinical governance perspectives. Further,

MDR-TB treatment is significantly more expensive than treating drug-sensitive TB, and expanding diagnosis and treatment of drug-resistant TB puts a large strain on limited national health budgets. In 2016, WHO began recommending a new, shortened regimen for MDR-TB of

9–12 months that costs about $1000 per person, on par with the median price per patient for DS-

TB treatment; the uptake of this regimen is expected to lower the per-unit cost of treatment for

MDR-TB (WHO TB Report, 2017), and is expected to incentivize national TB programs to expand diagnosis and uptake of the shortened, and cheaper, treatment.

Figure 2. Estimated Prices of WHO-recommended Drug Regimens

Disease # drugs Length (mos.) Treatment success Cost

Drug-susceptible TB 4 6 >85% $40/person

Drug-resistant TB 5+ 20 54%+ $2,000-5,000

(pre-May 2016) /person

Drug-resistant TB 5+ 9-12 $1,000 /person

(May 2016 update)

Source: World Health Organization. (2017). Global TB Report 2017. Retrieved from: http://www.who.int/tb/publications/global_report/en/.

Engaging the Private Pharmaceutical Sector in TB Control

All of this points to the great and urgent medical need for new, safer, and more efficacious drugs and combination regimens that provide options for patients who cannot be treated with existing medications. As innovators with expertise in drug development, pharmaceutical companies are well-positioned to contribute to, and influence, progress in enabling shorter, safer, and more effective regimens.

In 2001, the UN Millennium Declaration, which established the UN Millennium

Development Goals, and the WHO Commission on Macroeconomics and Health recognized TB as a global health and development priority. High-profile global commitments like the MDGs,

21 and the development of global health partnerships meant to mobilize financing and stakeholders across sectors in service of global TB control have raised TB on the global political agenda and increased external financing for efforts to control TB.

The increase in funding commitments have coincided with, and driven by, the development of novel institutional mechanisms to coordinate global advocacy and funding efforts, and engage the private sector. In 1998, in her first speech after being elected as WHO

Director-General, Gro Harlem Brundtland said that WHO must “reach out to others,” specifying other UN agencies, international financial institutions, NGOs, and the private sector (Brundtland,

1998). Specifically with regards to the private sector, Brundtland described the importance of the private sector both in technology development and health care service provision and the need for

“open and constructive relations with the private sector and industry” (Brundtland, 1998). This invitation sparked the development of numerous global health partnerships between WHO and other health agencies and across sectors; notably, the 1999 study of pharmaceutical industry beliefs and barriers to investment mentioned earlier (Blanc & Nunn, 2000) followed this spirit of openness. Among the first and most prominent of these was the Stop TB Partnership, a multisectoral partnership which was conceptualized in 1998 to coordinate and advance the activities of the many provider, advocacy, and donor groups engaged in fighting TB. The Stop

TB Partnership and its sister organization, the Roll Back Malaria Partnership, were similarly novel departures from the WHO’s traditional leadership model and exclusive focus on engaging with national governments which ran their own national TB programs. Despite the pluralistic intentions of the Stop TB Partnership, it was initially housed and administered by the WHO’s

Global TB Programme itself, reflecting the WHO’s traditional tight and centralized control of

TB control policies and what some have described as the conservative approach of the TB

22 community more broadly. In 2011, a handful of leading voices from civil society, wrote that

“…part of the challenge in the struggle against tuberculosis has been an inability to leverage the skill-sets of global partners to work effectively together. Although the Stop TB Partnership was created to serve precisely this function, we think that one of the reasons it has not happened is that the Partnership has not had the independence and freedom to work effectively and to complement the significant normative and policy roles that WHO has played in the field” (TAG,

2011). Despite the subsequent relocation of the Stop TB Partnership under the auspices of the

UN Office for Special Project Services (UNOPS), the tension between the risks and benefits that novel global health partnerships posed to WHO are encapsulated in the schismatic relationship that has characterized the Stop TB Partnership and WHO’s leadership over the past decade.

Though the Stop TB Partnership was created to bridge sectors and harness the private sector’s capacity for technological innovation, experience over the past two decades highlights challenges of operating as a private sector entity in the TB context. These challenges including entrenched skepticism over the merits of industry participation, factional policy and political disagreements that could trip newcomers to the field, and an unclear role for the private sector in governance.

Further, though the private sector has been represented in the governance of the Stop TB

Partnership for almost the entire existence of the partnership, the vibrancy of the private sector membership engagement has waxed and waned – both as functions of companies’ interest, or lack thereof, in focusing on in TB, and availability of resources and enthusiasm within the Stop

TB Partnership to support private sector engagement (Holm, 2009).

Though total financing for TB care and prevention has increased for more than 10 years, predominantly supported by The Global Fund to Fight AIDS, Tuberculosis and Malaria and bilateral funding from the United States, WHO estimated that a $2.3 billion funding gap still

23 existed in 2017 (WHO, 2017). Donor governments with bilateral aid programs may also be interested in closing this funding gap as part of their development programs, and having recognized that airborne threats like TB constitute a national security threat, given that MDR-TB is both easily transmitted and expensive to treat. Further, rich countries could find an advantage in supporting the economic stability of high-burden countries where TB may be an economic drain on communities and emerging markets, and support domestic industries and companies producing TB-related commodities. For example, USAID has been instrumental in providing technical assistance for the GeneXpert diagnostic for drug-resistant TB developed by Cepheid

(Sunnyvale, CA), as well as for J&J’s bedaquiline. Foundations, like the Gates Foundation, serve an important role in providing catalytic funding to attract cross-sector participation to achieve social goals, convening cross-sector partners, and providing expertise to support socially oriented projects. However, the WHO has been clear in stating that a greater responsibility for TB control, including financing of TB R&D, must be borne by governments of countries with high burdens of TB, who are accountable to their citizens’ right to health (WHO, 2017).

Global health systems have also focused on engaging pharmaceutical companies to improve access to medicines in low- and middle-income countries. According to the WHO framework for health systems, a well-functioning health system ensures equitable access to essential medical products, vaccines, and technologies of assured quality, safety, efficacy, and cost-effectiveness, and their scientifically sound and cost-effective use (WHO, 2007). WHO defines essential medicines as those that “satisfy the priority health care needs of the population”, which are intended to be available within the context of functioning health systems at all times, in adequate amounts, in the appropriate dosage, with assured quality, and at a price that individuals and the community can afford (Laing et al., 2003; WHO, 2007). The role of

24 pharmaceutical companies in ensuring access to essential medicines is reflected in Target 8.E of the Millennium Development Goals, which stated: “In cooperation with pharmaceutical companies, provide access to affordable essential drugs in developing countries”, with the United

Nationals Development Group defining access as “having medicines continuously available and affordable at public or private health facilities or medicine outlets that are within one hour’s walk of the population” (MDG Gap Task Force, 2008). This statement stressed the importance of stronger partnerships between pharmaceutical companies, governments, and civil society.

The basis for pharmaceutical companies to participate in access to medicine initiatives has also been articulated in terms of human rights and right-to-health frameworks. First referenced in the 1948 Universal Declaration of Human Rights, human rights are a set of obligations and international legal standards to which governments have agreed to promote and protect the rights of all individuals (UN, 1948). Health and human rights frameworks are based upon the recognition of rights and state obligations to respect, protect, and fulfill rights in relation to vulnerability to ill health and to policies and programs that affect health. In a 2008 report to the UN General Assembly, the UN Special Rapporteur Paul Hunt reported that though

“States have primary responsibility for ensuring both the right to the highest attainable standard of health and enhancing access to medicines,” it is also a “shared responsibility” with pharmaceutical companies. These calls for more robust accountability frameworks from the UN, academics, and civil society have not abated, and for a variety of reasons, pharmaceutical companies have responded to the MDGs, UN attention to the issue of access to medicines, and the subsequent SDGs, with increased engagement in neglected diseases and access to medicines over the past two decades.

However, the fundamental problem remains: the cost of developing new drugs and regimens is high and the populations in greatest need are poor people in low- and middle-income countries, so drug development presents an enormous challenge.

Part III: Incentives for Pharmaceutical Engagement

The WHO End TB Strategy set the ambitious aim of ending the global TB epidemic by

2035. One of the three main pillars of action focuses on accelerated discovery, development, and deployment of new tools and technologies (WHO, 2015). In order to accelerate the rate of incidence reduction from its current rate of 1.5% each year, two major inflection points need to be achieved by: (1) Optimizing use of current and new tools emerging from pipeline, pursue universal health coverage and social protection in order to end the curve so that incidence rates start declining at 10% per year by 2025; and (2) Introducing new tools, including a vaccine, new drugs & treatment regimens for treatment of active TB disease and latent TB infection, and a point-of-care test (WHO, 2015).

Without new effective tools it will not be possible to accelerate incidence decline at 17% per year, necessary to achieve the 2035 targets (Schito et al., 2015; WHO, 2015). Given the status quo of treatment options for TB, particularly complicated and toxic regimens of up to 24 months for people with drug-resistant TB and the lack of options for people with extensively drug resistant TB, new treatments are desperately needed. There are many goals for developing new drugs for TB, primarily to provide more drug options, more effective treatment, improved safety and tolerability, shorter treatment durations, and simplified regimens. Pharmaceutical companies continue to play a significant role, and can play a greater role, given these ambitious goals for new drug and treatment regimens.

Overview of the Pharmaceutical Industry

The 20th century’s convergence of scientific development, industrialization, and globalization has contributed to the emergence of a multinational pharmaceutical industry dominated by several large, for-profit pharmaceutical companies, collectively referred to as “Big

Pharma”. This industry has great R&D capacity to invent and produce drugs to treat serious health problems. However, since the 1970s, this R&D system has focused on generating drugs with a high revenue potential, such as high-earning “blockbuster” drugs, or drugs with a lower cost or risk during the development or regulatory process, such as modifications of existing drugs. Further, Big Pharma is motivated to concentrate primarily on the health issues of the world’s rich countries. The success of this bottom-line driven model is evident in the fact that pharmaceutical companies are among the most profitable in the United States, where they are able to charge high prices, maximize earnings from their most successful products, and deliver high returns for their shareholders. According to a calculation by the Government Accountability

Office (GAO, 2015), between 2006 and 2015, estimated aggregate worldwide pharmaceutical and biotechnology sales revenue for drug companies grew 45% (from $534 billion to $775 billion in real 2015 dollars). The largest 25 of these companies accounted for about 73% of the total 2015 pharmaceutical and biotechnology revenues, and the five largest companies accounted for a third of this figure. The GAO further estimated that average profit margins also grew from

2006 to reach about 17.1% in 2015 for all drug companies, though the largest 25 companies saw average profit margins of 20.1% in 2015 while all others firms saw an average profit margin of

8.6%. For context, the 25 largest software companies, an industry often used to compare with pharmaceuticals given high R&D investments and low production and distribution costs, saw an average, stable profit margin of 21.7% starting in 2006, that dipped to 13.4% in 2015; among the

27 largest 500 companies in other industries, the average profit margin decreased from 8.9% in

2006 to 6.7% in 2015.So, the pharmaceutical industry is not only highly profitable, but among the most profitable industries in the world, with the highest profits concentrated among the largest companies.

This profitability has been achieved with assistance from government protections, particularly intellectual property rights. As mentioned earlier, the drug development process is long and expensive, consisting of several main stages – basic research, drug discovery, preclinical testing, clinical trials, regulatory review and approval, and post-approval monitoring

(GAO, 2015). To incentivize innovation in spite of high upfront expenditure, a system of patents and market exclusivities exist to offer companies market power on new products and monopoly profits that cover R&D costs and generate a return on investment (Sloan & Hsieh, 2007). Patents are granted by the United States Patent and Trademark Office early in the R&D process, and exclude other companies from making, using, or selling the patented aspect of the drug for the term of the patent. Exclusive marketing rights, independent of patents, are granted for new FDA- approved drugs, during which the FDA cannot approve a similar version of the drug for marketing.

These barriers to market entry are time-limited, however. When brand-name drug products’ patents and exclusivity periods end, similar versions of drugs, known as “generics” for chemically synthesized drugs and “biosimilars” for biologics, may enter the market (GAO,

2015). The Drug Price Competition and Patent Term Restoration Act of 1984 (Hatch-Waxman

Amendments) facilitated earlier and less expensive entry of competitive drugs, which only have to demonstrate equivalence or high similarity to approved brand-name drugs and biologics,

28 respectively. This patent and market exclusivity system increases pressure for pharmaceutical companies to charge high prices for the duration of their monopolies to recoup high R&D costs.

The government is highly motivated to shape and regulate the pharmaceutical industry given its “dual roles”: (1) as drivers of comparative advantage, technological innovation, and growth in the economic sector, and (2) as factors contributing to both costs and health outcomes in the health sector (Sloan & Hsieh, 2007). As a result, developed countries, where most pharmaceutical companies are concentrated, are highly involved in the pharmaceutical sector. In the United States, the federal government is involved in several aspects of the drug supply chain.

Drug companies must apply and receive approval from the FDA to verify that their drugs are safe and effective in order to market drugs in the United States, providing quality protections to consumers and some liability relief for firms. Further, the federal government supports R&D for new drugs, such as through grants by the National Institutes of Health, National Science

Foundation, and other agencies. Notably, global R&D spending paid for and performed by pharmaceutical companies decreased from $6.7 billion in 2008 to $58.2 billion in 2014, and as a share of total global R&D spending; at the same time, a growing percentage of R&D was paid for by companies and performed by others, such as academics and smaller biotechnology- focused companies (GAO, 2015). The Internal Revenue Service (IRS) also offers tax incentives to encourage R&D.

Pharmaceutical companies have attracted intense criticism for their focus on marketing to maintain market share, lobbying to protect commercial interests, and defending intellectual property claims (Angell, 2004). All together, these characteristics of large, multinational pharmaceutical companies contribute to innovation that is primarily focused on health needs in rich countries.

Private pharmaceutical companies, which make up the bulk of the large multinationals, are primarily profit-motivated. Though they may possess the resources and reach to further the

TB control agenda, traditional market-based exclusivity incentives fail to attract their attention to global public health issues TB. Unsurprisingly, profiles of those affected by TB, namely the poor from low and middle-income countries, are not the target customer base that can adequately justify the enormous R&D investments by pharmaceutical companies.

Pharmaceutical companies would prefer to invest in diseases that affect people who can pay for medications and will be taking those medications for an extended period of time – not diseases that affect small markets or those with low willingness to pay. The pharmaceutical market has traditionally focused on the “blockbuster model,” where companies identify medicines that can be given on a periodic basis and generate large amounts of revenue. Lipitor is a classic example of a blockbuster drug, since it can charge a significant amount of money for the drug and patients must take the drug every day. In contrast, companies making drugs for tuberculosis do not earn recurring revenue from individual patients, even though the treatment regimen lasts months; the disease itself is still considered episodic, since people with TB will presumably be cured after taking a full and appropriate course of medication. The pharmaceutical industry argues that R&D is too expensive and risky to invest in low-return diseases. The Pharmaceutical Research and Manufacturers of America (PhRMA), a pharmaceutical industry association, suggests that it takes at least ten years to move a medicine from discovery to the marketplace, and that less than 12% of drugs that enter clinical testing will be approved (PhRMA, 2015). Estimates of the costs to bring a new chemical entity to market range from EUR 10-40 million for an improved treatment and EUR 100-150 million for a new chemical entity (DNDi, 2013) to $2 billion (Adams & Brantner, 2006), but are highly

30 contentious because they are often used to justify high pharmaceutical prices and market protections like patents. Given the high cost of development, low likelihood of success, and long drug development process, pharmaceutical companies are careful in picking their areas of investment.

Misaligned Incentives Deter Pharmaceutical Companies from Investing in TB Research &

Development

In 1999, the WHO’s STOP TB Initiative and the Special Programme for Research and

Training in Tropical Diseases surveyed 19 pharmaceutical companies to identify deterrents to tuberculosis research and gain insight into corporate priorities (Blanc and Nunn, 2000). Like this

DELTA project, this initiative was premised upon the belief that greater understanding of pharmaceutical industry values could inform and guide public sector actions to improve technological innovation for TB. The primary disincentive identified was the absence of financial opportunity, due to high investment and lack of perceived commercial return (Blanc and Nunn, 2000). This was undergirded by several core beliefs about this lack of profitability: the expensive drug development process, the small and uncertain market, lack of medical need given existence of cheap and effective drugs, and strong pressure to offer low prices (Blanc and

Nunn, 2000).

Expensive Drug Development Process

Developing a new drug “from molecule to market” is a complex, logistic process that requires decision-making in the face of great uncertainty and risk, particularly during early development of novel medicines (Klofsten, 2005). New chemical entities, new molecules that

31 emerge with activity against specific and promising molecular targets, are tested to understand their safety, efficacy, toxicity, pharmacokinetics, and metabolism before they can be approved and considered safe enough to test in humans (Hedner et al., 2010). Human trials include three phases of clinical tests in human volunteers and patients before an application for marketing approval can be made with a new drug application.

In 1998, the pharmaceutical industry estimated that the average cost of developing a TB drug ranged from $300 to $500 million (Blanc and Nunn, 2000). As mentioned earlier, the estimated costs of drug development have varied widely since this estimate, and is an issue of great controversy, since pharmaceutical companies looking to justify high prices often refer to this cost as the price of innovation. The industry estimate included both price of investment - driven by the high and growing cost clinical trials - and associated opportunity costs. TB offered uncertain and low financial rewards relative to other therapeutic areas, and given the highly competitive landscape and limits on market exclusivity, most companies wanted to recoup investment and profit quickly by focusing on “big hitters” that could earn $1 billion at peak sales

(Blanc & Nunn, 2000).

A Small and Uncertain Market

Economic research has found a strong, positive empirical association between potential market size and the entry of non-generic drugs or new molecular entities (Acemoglu & Linn,

2004). One of the biggest hurdles in catalyzing robust private sector engagement in TB is the small size of the addressable market. There are clear disincentives for large, for-profit pharmaceutical companies to invest in anti-TB drugs. The TB drug market is small and

32 fragmented, with multiple drugs required for combination regimens and a multiplicity of suppliers (TB Alliance, 2007).

The blockbuster model for pharmaceutical drug development encourages development of drugs that will be used for chronic conditions, rather than episodic, one-time cures. When it comes to developing antibiotics, social returns from antibiotic development is greater than private returns (Sertkaya et al., 2014). This market failure is demonstrated by the fact that many for-profit pharmaceutical companies have little interest in developing antibiotics, in general

(Projan, 2003). Reflecting low private sector interest in the broader anti-infectives field, there are few assessments of the value of the global TB market. In 1999, the industry estimated that the tuberculosis market was less than $150 million, and made less attractive because tuberculosis is declining in high-income countries, 95% of cases are in developing countries, and the disease primarily affects the poor who are unable to pay high prices (Blanc and Nunn, 2000). A subsequent report by the TB Alliance, a public-private product development partnership, estimated in 2000 that the total market was worth between $413.5 and $470.5 million per year, including $275-$318 million in the worldwide private TB market, an estimated $125-$140 million tender market, and an estimated $12.5 million for drugs to treat MDR-TB (TB Alliance,

2000). The TB Alliance expected the market to grow between $612 million and $663 million by

2010, identifying several factors, including expansion of TB control programs, and increasing coverage and treatment of MDR-TB and latent TB (TB Alliance, 2000).

The TB Alliance updated this estimate in 2007, based on in-depth studies of 10 key markets: Brazil, China, India, Indonesia, the Philippines, South Africa, which together comprised about the bulk of the global TB burden; and France, Japan, the UK and the US for which a global estimate of the market for first-line TB drugs by the TB Alliance ranged from $261 to $418

33 million (2007). Calculating a global market was more complicated for second-line drugs, given the large variance in regimens and medicines that may be prescribed based on varying drug- resistant patterns, long treatment periods and high toxicity contributing to high rates of loss-to- follow-up and regimen changes (Yadav/NASEM, 2012). The TB Alliance could only estimate the value of the second-line TB drug market across the 10 countries, which was, in total, only

$54 million (TB Alliance, 2007). Unlike HIV, TB impacts a very small number of people in high-income countries: combined, France, Japan, the UK, and the US account for 61% of the total global pharmaceutical market, but purchase less than $50 million worth of TB drugs (TB

Alliance, 2007).

TB drug markets could potentially grow, but there are major hurdles, including poor detection of drug resistance and treatment initiation, restricted access to second-line drugs in certain countries (especially China and India), and expensive, out-of-pocket payments to the private sector that severely limit access for most patients with drug resistant strains (TB Alliance,

2007).

Lack of Imminent Medical Need

The WHO’s endorsed first-line TB treatment regimen and affiliated package of interventions (DOTS), can cure tuberculosis if it is delivered appropriately and the treatment is completed. Given the existence of a cure, particularly WHO’s optimism about the strength and effectiveness of DOTS, there is even less incentive for pharmaceutical companies to develop an additional treatment (WHO, 2000). Anti-TB drugs face high levels of competition from cheap, established generics, since the majority of first- and second-line anti-TB drugs used today, like most antibiotics, were discovered in the mid-20th century (Coates & Hu, 2007). Further, concerns

34 about antibiotic resistance mean that new antibiotics are stewarded more carefully, which may include limitations on use (O’Neill, 2016).

Additional disincentives included the biologic difficulty and expense of targeting

Mycobacterium tuberculosis, the lengthy and costly development process, the risk of patent violations, the reservation of drug agents solely for TB treatment, and an aversion to working with governments (Blanc and Nunn, 2000). As the case study on bedaquiline demonstrates, all of these barriers continue to impact pharmaceutical companies’ decisions to invest in TB today.

Creating a Reason to Develop New Drugs for TB

When pharmaceutical companies do make significant investments in diseases that mostly affect poor people in poor countries and take steps to increase access in those markets, it is important to understand their motives. The most obvious stimulus for pharmaceutical companies to invest in drugs are policy incentives offered by governments and private foundations that change the economics of making such investments. However, a multi-pronged approach is needed to engage industry in new drug development, with leadership by the public sector and

WHO, since there is no natural incentive for private industry to invest in anti-TB. These recommendations included building relationships, trust, and communications with industry, using WHO’s convening power to generate ideas and disseminate knowledge, acknowledge and protect the role of markets and perceived market opportunity, and leverage expertise in R&D in developing countries to support development efforts (Blanc & Nunn, 2000). All of these, however, are suggestions that ran counter to WHO’s traditional operations, and these suggestions have not been adopted in full and have not worked to stimulate great increases in pharmaceutical companies’ interest in TB.

However, between other international institutions, national-level public regulators, and private foundations, several incentives have been devised to encourage pharmaceutical companies to develop drugs that address the needs of poor people in developing countries. These incentives can generally be understood as lowering the risk of investment for commercial actors, creating a reward for breakthrough developments, or fostering a market for these drugs, though they are also known more colloquially as “push” and “pull” incentives (Renwick et al., 2016).

Reich (2000) has also mentioned an additional “process” incentive: creation of institutional capacity.

Push Incentives: Lowering Risk

Push incentives tend to lower the cost of investment through collaborative open research models, providing grants, fellowships, and other funding for research, fast-tracking research processes, and offering relief from investments through research tax credits and incentives

(Renwick et al., 2016; Trouiller et al., 2002; Sinha & Kesselheim, 2016). These incentives are particularly attractive for lowering barriers to entry for smaller and medium-sized enterprises, which may lack the capital to fund advanced clinical development, and increasing collaboration at an earlier stage (Renwick et al., 2016). Further, push incentives can be discretely tied to various stages of R&D to ensure aligned development pace and priorities (Renwick et al., 2016).

The value of early-stage R&D payments has also been estimated to be higher than the value of an equally-sized “pull” incentive later, with Spellberg et al. (2012) suggesting that an early-stage push could be up to 95% smaller than an equally effective reward given later. However, push incentives often require a large upfront outlay of financial resources, and since these investments have long lead times and do not guarantee successful projects (Renwick et al., 2016), push

36 incentives can appear risky and may be more attractive for small grants and rewards. Further, the structure of push incentives may constrain scientific innovation (Renwick et al., 2012), since the option for funders to predetermine targets and shepherd the process may run counter to creative scientific discovery.

Process Incentives: Increasing Institutional Capacity

A notable initiative launched by the WHO and administered through the Stop TB

Partnership is the Global Drug Facility (GDF), which was developed in response to member states’ demand for new international approaches to ensure access to and efficient national procurement and distribution of drugs to treat TB, declared at the Ministerial Conference on TB and Sustainable Development in Amsterdam in 2000 (Matiru & Ryan, 2007). As a key part of the WHO strategy to achieve global targets to reduce the burden of TB, the GDF was established to ensure that each country’s national TB control program had access to high-quality anti-TB drugs to expand and implement the WHO-recommended DOTS strategy for controlling TB, while stimulating political and public support in countries worldwide for public funding of anti-

TB drug supplies (Matiru & Ryan, 2007). The Green Light Committee, an expert advisory group, was created in 2000 to ensure access to second-line TB drugs in response to rising prevalence of

MDR-TB, with second-line drugs routed through the GDF. Today, the GDF is the largest public sector supplier of quality-assured anti-TB drugs (including first-line, second-line, and pediatric) in the world, and leverages its pooled procurement to demand lower cost drugs. The GDF is an important mechanism for simplifying procurement, not only for national TB programs but also for private companies looking to distribute their medical products through a centralized, legitimate system.

Alongside the Stop TB Partnership and the Global Drug Facility’s efforts to connect the

WHO Global TB Progamme to the private sector, private foundations, national governments, international financial institutions, and private companies have also convened to stimulate TB control.

One of the most important market-shaping incentives have arisen with the rise of global public-private partnerships to promote TB drug development, among other global health priorities (Buse & Walt, 2000). PDPs emerged to engage pharmaceutical companies with R&D for poverty-related diseases (Cole & Iyer, 2016; Topal, 2014). The original blueprint for these models can be seen in the Medicines for Malaria Venture established in 1999, which was supported by multiple governments as well as the World Bank and the Rockefeller Foundation to facilitate R&D for antimalarials (Cole & Iyer, 2016). PDPs work in three main ways: facilitating financial risk-sharing across the public and private sectors for R&D, catalyzing pharmaceutical industry engagement in open research collaborations with academia, and ensuring access to successful innovations is systematically considered early in product development (Topal, 2014).

PDPs can play an important role in leveraging corporate expertise for projects that are important but do not carry financial incentives for their stakeholders, attracting donors to pool funding mechanisms (Topal, 2014). Particular strengths include the ability of sponsors to set targets and guide development, non-profit aims that focus on accessibility of drugs, and pooled risk and expertise, which appeals to potential funders; however, there is no guarantee of success, and it can be difficult to manage the roles of multiple stakeholders with their own agendas in a transparent and viable manner (Renwick et al., 2016). PDPs appear to be working, with a 35% increase in company engagement with various PDPs and intellectual property sharing partnerships from 2012 to 2016 (Cole & Iyer, 2016).

Several PDPs focused on promoting R&D for TB were launched in the early 2000s. The most prominent among these are: the Global Alliance for TB Drug Development (TB Alliance), a non-profit accelerating discovery and development of new TB drugs and regimens, and currently houses the largest TB pipeline in history; the Aeras Foundation and the TB Vaccine

Initiative, which support most of the vaccine candidates that are currently in clinical trials (to replace the Bacillus Calmette-Guerin vaccine, which is only partially effective and used primarily in children); the Critical Path to TB Drug Regimens, which is facilitating early knowledge sharing so that potential regimens can be developed and tested when compounds are still in the preclinical development phase; and the Foundation For Innovative New Diagnostics, which creates new diagnostic tools, of which TB is part of its portfolio. In parallel, several large, multinational pharmaceutical companies have shifted their drug development efforts upstream to less expensive drug discovery stages that allow them to control costs when investing in diseases like TB that yield low shareholder returns (Moran, 2005). In making this shift, companies have relied on public PDPs to subsidize the more expensive and lengthy clinical trials, registration, and implementation stages (Moran, 2005). In this new structure, PDPs become “essential” to multinational company participation, and wear several hats: catalysts to firm involvement, coordinators of multiple partners throughout the pipeline, resource allocator of R&D funds based on public health needs, and manager of drug portfolios based on objective merits (Moran, 2005).

Product development partnerships have also been categorized as “push” strategies, given the role of sponsors. However, given their key role in the structural shift in non-profit and multisectoral production of medical products traditionally developed in the private sector, in addition to providing new modes of financing and incentives throughout the development process, these partnerships warrant separate consideration.

Pull Incentives: Attracting Investment

Pull incentives are focused on attracting investments by increasing or by promising later rewards. Unlike push incentives, which do not guarantee successful outcomes, these incentives only reward successful development, putting all of the risk of development upon the developer.

Pull incentives include advanced market commitments, or patent buyouts; alternatively, they may use legal and regulatory systems to offer accelerated approval, extend market exclusivity rights, or increase reimbursement prices (Renwick et al., 2016). These incentives tend to reward larger firms that can bear the financial risk of failure and expensive development in pursuit of such rewards, and require credible backers who can support long-term guarantees (Renwick et al., 2016). Further, it is hard to estimate sufficient rewards and set appropriate guidelines to guide development, and the use of legal and regulatory incentives, particularly intellectual property rights, can reduce innovation and do not guarantee accessibility of the drugs that are developed (Renwick et al., 2016).

One of the most controversial incentives in this category is the priority review voucher.

Priority review vouchers can be sold to other companies in the market, where such vouchers have been valued between $67 and $350 million (Gaffney et al., 2016). Priority review vouchers have attracted avid criticism for inefficiency and insufficient guardrails (Aurora et al., 2016;

Gaffney et al., 2016) ever since the FDA awarded Novartis with the first such voucher in 2007 for a drug, Coartem, that had already been registered in 1999 (Anderson, 2009). Many of the risks of pull incentives can be seen in the priority review voucher system, highlighting the importance of appropriate and careful interventions to ensure that incentives actually benefit health outcomes.

Given the range of players and policy incentives, typically a mix of push, pull, and process incentives are used; in fact there is growing consensus that hybrid strategies, both to comprehensively attract appropriate R&D and to develop sustainable funding, are required

(Renwick et al., 2016). For example, in the United States, the Orphan Drug Act of 1983 was introduced to incentivize drug development for rare diseases – defined as those that affect

200,000 patients or less, or for which drug development costs are unlikely to be recovered in the

United States (Swann, 2018). Orphan drug designation offers a mix of push and pull incentives:

7 years of market exclusivity enhances the commercial opportunity, a tax credit, and a waiver of the user fee associated with the application (FDA, 2011). In particular, the orphan drug tax credit allows companies to claim half of qualified clinical testing expenses, including foreign clinical testing expenses, for drugs that treat a specified list of diseases that affect fewer than 200,000 people in the United States or that affect more than 200,000 people but for which the manufacturers do not expect to recover development and marketing costs (GAO, 2015).

Companies have clearly responded to this incentive: from 2005 to 2014, many more companies have claimed this credit, with total claims increasing five-fold from $280 million to about $1.5 billion; the increased federal outlay to cover these costs corresponds with an increasing share of orphan-designated drugs from 4% of all drug approvals in 2005 to 21% in 2016 (GAO, 2015).

Clearly, policy incentives play an important role in changing the investment calculus of pharmaceutical companies considering investment in traditionally unprofitable drugs.

Nonfinancial Reasons for Pharmaceutical Companies to Invest in TB

Many companies have responded to public attention to the need for treatments for neglected diseases in ways that are neither mandated nor directly incentivized. Within the pharmaceutical

41 sector there is no consensus about which activities they “ought to” pursue or prioritize compared to what activities they “must” perform (Leisinger, 2009). As a result, many research-based pharmaceutical companies have committed to improving access to medicines in low- and middle-income countries through a variety of voluntary corporate strategies and partnerships

(Leisinger, 2009; AtMI, 2017). Droppert and Bennett (2015) found that the six highest earning pharmaceutical firms were engaged in many corporate social responsibility (CSR) activities in low- and middle-income countries. The most common CSR activities these firms cited were: using differential pricing strategies to lower the price of drugs for lower-income settings or populations, which requires ability to regulate arbitrage and accurately forecast the market; increasing local drug distribution infrastructure; support for SDGs; and targeting R&D investments to meet developing countries’ health needs (Leisinger, 2009; Droppert & Bennett,

2015). Notably, most of these activities involve partnerships and activities across the health value chain with other private for-profit entities, local governments, and local and international

NGOs. However, there is a lack of evidence about which activities are the most effective in improving health outcomes from a public health perspective.

From a firm perspective, such activities can be beneficial to long-term business strategy. These issues include: minimizing reputational risk due to growing pressure to meet the needs of developing countries; corporate social responsibility and ethics; and strategic considerations, such as positioning in emerging markets or accessing skilled researchers in developing countries

(Moran, 2005). In particular, the majority of pharmaceutical companies reported reputational benefits to customer perception and employee satisfaction (Droppert & Bennett, 2015).

Numerous studies show the extent to which Pharma’s reputation has declined since the 1990s: a recent Gallup poll found that half of all respondents had a somewhat negative or very negative

42 overall view of pharmaceutical companies (Gallup, 2017). For health companies like pharmaceutical companies that rely upon trust and perceived value to market their products and justify products, reputation is a critical asset. Reputational effects go hand in hand with a growing recognition that businesses have environmental and social responsibilities. As Droppert and Bennett (2015) have noted, while the UN has suggested that CSR offers opportunities for governments of middle and low-income countries to change the terms of business interactions and leverage additional resources through partnerships with business, the public health community does not yet Further, though corporate philanthropy is considered to offer some competitive advantage (Porter & Kramer, 2002), even the largest pharmaceutical companies have limited ability to maximize their resources and will toward global health priorities. Further, given the growing commercial importance of emerging markets, and the potential of developing relationships with key regulatory and market entry stakeholders and growing brand association with innovative products.

In summary, development of pharmaceuticals targeting TB continues to be market-driven, and as a result there has been little progress in TB treatment innovation. However, the past two decades have seen an uptick in the use of a variety of push, pull, and capacity-enhancing incentives, in addition to a growing appreciation for longer-term benefits to pharmaceutical companies investing in TB.

The Current State of Pharmaceutical Engagement

Despite the rosy picture of PDPs and evidence of multinational pharmaceutical companies’ engagement in various activities related to neglected disease research in the early

2000s, the landscape for TB has again shifted. Though multinational pharmaceutical companies

GlaxoSmithKline (Brentford, United Kingdom), Novartis (Basel, Switzerland), Pfizer (New

York City, New York), and AstraZeneca (Cambridge, United Kingdom) were praised at the start of the 21st century for developing dedicated infectious disease R&D units, three of these companies have closed their TB research programs since 2012, as part of a broader shift away from anti-infectives (Frick et al., 2016). By 2014, the pharmaceutical sector spent only $98.6 million on TB drug development, a third lower than spending in 2011, and Otsuka (Tokyo,

Japan) alone supplied 54% of all funding from the pharmaceutical industry (Frick, 2015).

Funding for TB R&D continues to have stagnated since the global financial crisis, and also continues to be concentrated among several key players: the public sector generates 60% of TB research funding, 62% of which comes from the United States ($248.5 million in 2014) – and the philanthropic sector, which is dominated (84%) by the Gates Foundation’s support (Frick et al.,

2016). However, despite the small relative investments in TB R&D by pharmaceutical companies, the major candidates for new drugs that have been repurposed or newly discovered have still originated from the private pharmaceutical sector.

For example, in 2009, a team at the Novartis Institute of Tropical Diseases in Singapore found a new class of compound, pyrimidine-imidazoles, which only blocked the ability of mycobacteria to survive in its glycerol suspension, demonstrating in vitro success but no impact on mice (Maxmen, 2013). Thomas Dick, who led the project at Novartis, described it, as “the failure of a two-year project that took a lot of investment” (Maxmen, 2013). Novartis subsequently dropped out of TB drug discovery, signing a deal in 2014 to hand over its experimental TB drugs to the TB Alliance (Copley, 2014). While the availability of the TB

Alliance to assume these abandoned efforts, which might have formerly been lost to the community, signals progress in the TB drug development landscape, the inherent tradeoff has

44 been the loss of further expertise and dedicated resources from Novartis to further TB drug development.

In 2013, Pfizer announced that it was withdrawing from early-stage TB R&D, after delaying progress on sutezolid, an antibiotic drug candidate with encouraging results in early studies. Pfizer sold its rights to the drug to a smaller company, Sequella, which some doubted had the capacity to fully develop the compound (Andrews, 2017). Johns Hopkins University almost sold its rights to sutezolid to Sequella in 2017, when a coalition of global health non- governmental organizations including student group Universities Allied for Essential Medicines,

Médecins Sans Frontieres’ Access Campaign, the Treatment Action Group, the Global TB

Community Advisory Board, Public Citizen, and university alumni pressured Johns Hopkins to license sutezolid to the Medicines Patent Pool, a mechanism for pooling voluntary licenses for

HIV/AIDS, TB, and hepatitis C drugs (Andrews, 2017). This marked the first time a TB drug was licensed to the MPP, and poses another potential alternative to private ownership and development. However, again, there are broader implications of Pfizer’s pivot away from TB, and antibiotics more generally, that remain to be seen in an era of high antimicrobial resistance, of with MDR-TB is one high-profile issue.

Further, in January 2014, AstraZeneca announced that it would shut a laboratory in India where it was conducting early-stage research into TB as well as malaria and neglected tropical diseases, sparing only AZD5847, a TB treatment in Phase II development. In 2010, AstraZeneca had partnered with the TB Alliance, pledging to collaborate on new tools; AstraZeneca’s Vice

President of Infection Discovery explained that “AstraZeneca is building a leading franchise in the treatment of infectious diseases, both through our own in-house research as well as through collaborations. This collaboration is part of the global partnership that will be needed to conquer

45 the TB epidemic” (TB Alliance, 2010). AstraZeneca had invested $10 million in tuberculosis

R&D in 2012, making the company the third largest private funder in global TB R&D (TAG

Pipeline Report, 2014). With this move, AstraZeneca, along with the other high-profile exits of major pharmaceutical companies from TB research and development, reaffirmed Big Pharma's reputation for only investing in drugs for high-income countries.

In the context of major failures of the pharmaceutical industry to continue to develop TB drugs, there are lessons we can learn from those major pharmaceutical companies that have continued to pursue new treatments and regimens to treat TB: Johnson & Johnson and Otsuka.

My focus on Johnson & Johnson’s experience developing a new drug for TB, bedaquiline (brand name SIRTURO®), and highlighting key considerations for pursuing the development of bedaquiline stems from my placement during my within Johnson & Johnson’s Global Public

Health team, from which I gained multiple perspectives on policy and partnership priorities for continuing to develop the drug, the company’s intentions and efforts to increase market access to the drug, and the local, national, and global public health system’s response to the introduction and expanded access to the drug.

Part IV: A Bright Spot for TB Drug Development – J&J’s Development of Bedaquiline

The need for new TB treatment options is clear: the global burden of TB is unlikely to decline without new tools, and current treatment regimens are insufficient, especially to treat drug-resistant strains. In the context of a motley set of incentives that the public and philanthropic sectors have developed to incentivize TB drug development, it is unclear how pharmaceutical companies perceive these piecemeal incentives when balancing them with clear disincentives. The withdrawal of several large multinational companies from TB R&D suggests

46 that these incentives may not be sufficient, aside from potentially offering continuity when companies decide to withdraw from the field. However, in 2012, J&J received approval for a new drug to treat MDR-TB, bedaquiline (SIRTURO®). Why?

Johnson & Johnson’s path to the discovery, development, and dissemination of bedaquiline was unlikely. The availability of key incentives and long-term motivations served as key facilitators to enable the company’s continued investment in the drug, as well as Johnson &

Johnson’s continued engagement in bringing bedaquiline to market. However, the origins of how bedaquiline came to be approved, with a lower standard of evidence than traditionally required of regulatory agencies today, and the way that the company decided to structure the Global

Public Health organization that would house and shepherd the drug’s market access strategy reflect the tensions facing profit-motivated pharmaceutical companies that invest in drugs with low commercial value. These issues are not easily overcome – and as this case study describes, several key factors contributed to Johnson & Johnson’s commitment to continuing to develop bedaquiline: unconventional leadership from scientists able to navigate a complex research organization and system, key regulatory incentives designed to ease the financial burden of R&D into new drugs, and growing, and timely societal and internal pressures to demonstrate corporate responsibility that created non-financial incentives. Further, this case study goes on to demonstrate the key, but narrow, role that pharmaceutical companies play in making new drugs accessible to populations that need them, as well as the limitations these companies face when operating within broader public health systems and contexts. Though bedaquiline’s roll-out is still ongoing, and we are only five years out from its FDA approval, this case study describes barriers and facilitators to date in investing in TB, continued challenges in making the drug accessible, and implications for the public health field.

Background on Johnson & Johnson

Johnson & Johnson (J&J) is an American multinational medical device, pharmaceutical and consumer packaged goods manufacturing company headquartered in New Brunswick, New

Jersey, and incorporated in 1887. J&J is a holding company, with three business segments –

Consumer, Pharmaceutical and Medical Devices – and more than 260 operating companies and

134,000 employees in virtually every country in the world (J&J Annual Report, 2017).

J&J’s pharmaceutical segment is a major driver of the company’s growth, and in 2017, the company invested $10.6 billion in R&D (J&J Annual Report, 2017). J&J focuses on six therapeutic areas: immunology (e.g., rheumatoid arthritis, inflammatory bowel disease and psoriasis), infectious diseases and vaccines (e.g., HIV/AIDS), neuroscience (e.g., mood disorders and schizophrenia), oncology (e.g., prostate cancer and hematologic malignancies), cardiovascular and metabolism (e.g., thrombosis and diabetes), and pulmonary hypertension

(e.g., Pulmonary Arterial Hypertension), a new therapeutic area which was established with the acquisition of Actelion in June 2017 (J&J Annual Report, 2017). J&J earns significant profits from its blockbuster drug, REMICADE ® (infliximab), which accounted for approximately 8.3% of the company's total net trade sales in 2017 (J&J Annual Report, 2017), highlighting the importance of profitable pharmaceutical investments.

Even as J&J looks to generate significant returns to shareholders, the company maintains a reputation for being a values-driven company. J&J’s mission and values are famously articulated in a company credo originally crafted in 1943 by then-CEO Robert W. Johnson. In four paragraphs, “Our Credo” affirms the company’s responsibility to its customers and those who use their products and services, employees, communities, and shareholders, in that order

(J&J website, 2017). J&J regularly performs well on reputational metrics and outscores its

48 pharmaceutical industry competitors, with its consumer healthcare products like Band-Aids and

Baby Shampoo ameliorating some of the reputational drag of the unpopular pharmaceutical industry (Bulik, 2017). For example, in 2017, J&J was recognized on the Fortune Change the

World list and Fortune’s Most Admired Companies lists. J&J has strived to be a leader in corporate social responsibility, and houses a corporate-level philanthropy arm (Global

Community Impact).

Despite the significance of the pharmaceutical business for J&J and its identification with corporate social responsibility, developing new drugs for a disease like TB was still unlikely.

Bedaquiline was discovered at Janssen Pharmaceutica, a pharmaceutical subsidiary of J&J which employs a total of more than 40,000 people in 150 countries (Janssen website). Janssen

Pharmaceutica was founded by Paul Janssen in 1956. His company’s discovery and commercialization of breakthrough compounds like Haldol, the first antipsychotic that allowed patients to be treated at home instead of in institutions, and fentanyl, a widely used anesthetic today. Today, bedaquiline is so ingrained in the Janssen public narrative today that the description of Dr. Paul Janssen, a renowned researcher and founder of Janssen Pharmaceutica, on

Janssen’s website reads: “One of his last dreams was to find a medicine to treat multidrug- resistant tuberculosis.”

Case Study: Developing Bedaquiline

The Importance of Champions

In many ways, bedaquiline’s existence can be credited to an intrepid group of curious scientists who were able to navigate both the scientific hurdles presented by Mycobacterium tuberculosis and the broader systems – within Janssen, J&J, and the broader TB innovation ecosystem – in which they operated. When a lone scientist began screening for TB in a Janssen

49 laboratory in the 1990s, the company did not have a drug pipeline focused on tuberculosis or other neglected diseases. There was a drug donation program for a drug discovered in the 1970s by Paul Janssen (flubendazole) to treat soil-transmitted helminths, and later, in 2001, Janssen acquired a start-up called Tibotec, whose lead compounds focused on treating drug-resistant

HIV/AIDS. However, HIV, unlike TB, has a significant market in high-income countries and the business rationale for R&D investments in HIV were self-evident.

This scientist had heard WHO’s announcement that TB was once again a global health crisis, and became curious about the disease. In the absence of the expensive containment laboratories that are required to work with Mycobacterium tuberculosis itself, he began a pet project to test a non-pathogenic, environmental species of mycobacteria, Mycobacteria smegmatis (Lougheed, 2017). This alternative bacterium that is easier to handle, grows faster than Mycobacterium tuberculosis, is now widely used to understand Mycobacterium tuberculosis, and has a similar susceptibility profile to MDR-TB (Nguta et al., 2015), making it a resourceful choice for this enterprising individual, who integrated its testing into routine compound screens: every time his team ran a plate of potential new compounds, they also screened compounds against Mycobacterium smegmatis (Lougheed, 2017).

A more sophisticated drug discovery apparatus would likely have bypassed this antiquated approach and, as later, failed TB drug discovery efforts have shown, may not have been as successful. The antimycobacterial drugs that continue to be used today were mostly discovered through this type of blind screening process, in which a high volume of compounds were tested against the whole bacteria (Nguta et al., 2015). While this screening approach was common in the mid-20th century, by the 1990s, it was considered to be quaint in the face of new drug discovery techniques (Swinney, 2013; Andries et al., 2005). At the end of the day, success

50 of this process came down to luck. There was no guarantee that the same compound successfully tested against Mycobacterium smegmatis would be effective against Mycobacterium tuberculosis

(Lougheed, 2017). This project continued until over 10,000 compounds had been screened against Mycobacterium smegmatis, until one of them appeared to work (Lougheed, 2017).

Koen Andries, a trained veterinarian who became responsible for the program in 2001, recognized early on that bedaquiline would face many challenges, which he has noted in a later interview with The Financial Times, saying, “We were a bit prudent in being quiet for some time. If you ask upfront, there is a high risk of many people saying no. We kept it under the table till we had really convincing data” (Jack, 2013). This quote demonstrates an intuitive caution and political sophistication that Andries and his team possessed. As Andries suggested in another media interview, the team was highly aware of the lack of market potential of a new drug for TB, and said “You really need a strong champion to defend a compound without a return on investment so getting it through that period was an enormous challenge” (Coleman, 2014).

Authorization from Management

According to Andries in a later, published interview, it was sheer persistence and the ability to convince the heads of R&D to stay the course that secured the eventual success of the project after almost 15 years (Coleman, 2014). Over this time, within Janssen, R207910 was internally transferred to Tibotec, where it was renamed TMC207 (J&J Annual Report, 2004). While the culture of Tibotec may have been more entrepreneurial, it was still a business. Though it had gained success by focusing on HIV drug resistance, the difference between HIV and TB was that an HIV product line could still be sustainable due to cross-selling opportunities in rich countries, which could offset low price-points for the product in less lucrative markets. It did not take

51 sophisticated analysis and modelling to realize that TB, particularly affecting developing countries, had no prospect of a return on investment.

Even, or especially, within a large, decentralized company like J&J, R&D for pharmaceuticals operates with a set budget. Resources that were being dedicated to bedaquiline (TMC207) could have been used to pursue other projects that were more commercially viable. In this context of a highly competitive internal environment, where success and resource allocation are defined by sales and profitability, a drug like bedaquiline did not align with the broader organization’s goals or commercial model.

The dance between the bedaquiline team and management, which had the authority to make go/no-go decisions, left bedaquiline’s fate in a precarious state. Scientific appeals, though, would be strengthened by demonstrations of scientific promise, since no one would consciously bet on a losing horse. Though preclinical trials had demonstrated promising results, scientific setbacks in risky clinical trials threatened to become existential challenges.

Even the most dedicated scientists could not have proceeded without authorization from management, who had to decide once the efficacy was demonstrated. By 2009, Tibotec Inc. had created a new Global Access and Partnerships program, which was creating a sustainable portfolio of medicines designed to address major health challenges in resource-poor countries.

Some clues as to what the leadership may have been thinking can be surmised from some quotes by Stoffels, when interviewed by The Financial Times about why J&J had decided to develop a drug for TB (Jack, 2013), even as competitors with early stage treatments (like Pfizer and

AstraZeneca) were withdrawing from infectious diseases:

 “It is a historic discovery to find a new target for such an important disease. You can’t

just leave it there. Somebody had to take it on.” J&J prides itself on its corporate

responsibility, per the company’s Credo, and leadership.

 “A company consists of people, who may decide to pursue something they consider

important.” Employee engagement is critical to business functioning, and decentralized

innovation may bear fruit in other ways.

 “All together we came to the conclusion that, even if we don’t earn a lot of money [from

the drug], we won’t lose a lot and it will make a huge difference in the world.” While TB

may not represent a commercial gain, there is also no significant cost involved.

These explanations all correspond with the multiplicity of reasons for companies to continue to develop the drug, as described in findings from Droppert and Bennett (2015) and Moran (2005) discussed earlier.

Letting the data speak for itself

Preclinical trials proceeded slowly, given the slow growth of the Mycobacterium tuberculosis and the complex biology of the bacterium which made it hard to identify the mechanism of action. In 2003, trials on mice demonstrated “spectacular” results, with the identified compound, a diarylquinoline, outperforming a combination of the three best tuberculosis medicines of that time (Furniere, 2014). The next year, the researchers discovered the mechanism of action and published their findings in Science; these have been cited over 1500 times as of March 2018. Unlike any other anti-TB drug on the market, R207910 destroyed the bacteria by shutting down their energy supply unlike other TB treatments that focus on slowing the development of new bacteria (Lougheed, 2017). More specifically, most existing drugs used

53 to treat TB and MDR-TB targeted either the cell wall or RNA of the tuberculosis bacteria to slow its reproduction, lowering infection levels over time. This new diarylquinoline was the first drug to interfere with its metabolism by targeting the enzyme ATP synthase, paralyzing energy production in the bacterial cell, which then dies. Most importantly, since the drug acted through a novel mechanism of action, it could be active against all drug-resistant strains of TB.

The discovery was met with huge excitement in the TB research and development community. R207010, later called TMC207, was “the darling of the TB community” and even the WHO, which would be a key stakeholder in setting guidelines down the line, took note of the promising medicine (Marris, 2005). “There was also a refreshing sense of forward movement”

(Barry, 2009) and a shake-up to previous assumptions in a field that had seen no progress on new drugs for decades.

It would take several more years to develop the drugs, a road which included numerous setbacks. For example, after a one-week early bactericidal activity study that attempted to demonstrate efficacy in two sites in South Africa had an underwhelming result (Rustomjee et al.,

2008), development of the drug almost came to a stop (Coleman, 2014). Early bactericidal activity studies measure the ability of a single anti-TB agent, in this case bedaquiline, to kill rapidly metabolizing mycobacteria present in tuberculous pulmonary cavities and evaluate short- term toxicity and dose-ranging of TB drugs. The TMC207 doses were only observed to have any activity after four days, compared to immediate activity of the other two randomized treatments of first-line staple TB drugs, isoniazid and rifampin. At the end of seven days, bedaquiline, when delivered as a monotherapy, had a statistically significant but very similar magnitude of effect to isoniazid and rifampin (Rustomjee et al., 2008). However, since early bactericidal activity studies are traditionally carried out over 2 days, this pivotal test could have ended before any

54 effect could be shown. The scientists were able to attribute the effect to delayed action seen in earlier tests in animals (Rustomjee et al., 2008). The slim advantage of administering once-daily oral TMC207 demonstrated in this trial, along with the sometimes arbitrary conventions of drug development, highlight the riskiness and challenges of searching for new drugs and looking for evidence of efficacy and safety.

The team was also able to convince management to do one more study, which formed an eight-week, first stage of a Phase 2 trial (Diacon et al., 2009), an open-label, single-arm trial to evaluate the safety, tolerability, and efficacy of TMC207 as part of an individualized MDR-TB treatment regimen in subjects with pulmonary MDR-TB. Though this first stage was not sufficiently powered (n=47), the results of this trial, published in the New England Journal of

Medicine, demonstrated dramatic effectiveness. The addition of TMC207 to standard therapy for multidrug-resistant tuberculosis reduced the time to conversion to a negative sputum culture, as compared with placebo, and increased the proportion of patients with conversion of sputum culture (48% vs. 9%) by the end of the eight weeks (Diacon et al., 2009). Considering that

WHO-recommended treatment at the time required 20 to 24 months of treatment, the clear demonstration of efficacy in just two months was remarkable.

Though Phase 2 clinical trials generally demonstrated remarkable efficacy of the

TMC207, with a slight risk of QT prolongation, which creates irregularities in the heart, a more problematic result came in the second stage of the Phase II clinical trial (Diacon et al., 2009).

This trial revealed a disturbing morality imbalance, in which more people tested with bedaquiline died during the two-year follow-up period than people in the placebo group: in total, nine patients who received bedaquiline died over the course of the two-year trial, compared with two patients who received a placebo. Only five of the deaths in the group that received bedaquiline

55 and all of the deaths in the placebo arm appeared related to tuberculosis, but no consistent reason could be identified for the deaths in the remaining bedaquiline-treated patients (Diacon et al.,

2009; Cox & Laessig, 2014). The unexpected finding posed an important concern, and would cast a long shadow on bedaquiline’s approval and post-approval requirements. An in-depth post- mortem with outside experts suggested a few potential explanations: fewer people in the placebo arm had died than typically would have in real-world conditions, the so-called “tyranny of small numbers” may have allowed for this unexpected result due to the small sample size, and there was a muddled causal relationship between bedaquiline and the deaths due to long follow-up.

From the shadow of these unfavorable results, however, J&J submitted an application for a conditional approval for bedaquiline, proposing to treat adult patients infected with pulmonary tuberculosis due to MDR-TB.

Legal and Regulatory Incentives Support J&J’s Engagement, With Unanticipated Consequences

On July 2, 2012, Janssen announced that it had submitted a New Drug Application

(NDA) to the U.S. FDA seeking accelerated approval. The accelerated approval mechanism authorized by Congress in 1992 (FDA, 1992) allowed the FDA to speed up the approval process for bedaquiline based only on a two-stage phase II trial. Bedaquiline met the three requirements for accelerated approval: prove the drug treated a serious condition, provide meaningful advantage over currently available therapies, and demonstrate an effect based on a surrogate endpoint (a biomarker that is likely to predict a clinical benefit; substitute for a clinical endpoint)

(FDA.gov). Though the mortality imbalance discovered in the second stage of the Phase 2 clinical trial created significant uncertainty, ultimately, the FDA approved bedaquiline on

December 28, 2012.

Bedaquiline became the first stringent regulatory authority to approve a new mechanism of action for tuberculosis in over 40 years. The indication of use for bedaquiline was limited to treatment of adults with multidrug-resistant pulmonary tuberculosis for whom an effective treatment regimen is not otherwise available, a population it deemed to have “considerable unmet need and a positive benefit–risk balance” (Cox & Laessig, 2013). The FDA also assigned bedaquiline with a “black box warning” that informed patients and health care professionals about potential deaths in people using the drug.

Despite the limitation of bedaquiline to a last-resort status, as well as the black box warning, approval came with several key advantages for J&J. The FDA simultaneously granted

J&J a suite of mechanisms and rewards designed to incentivize investment in neglected diseases: accelerated approval, orphan drug status, and a tropical disease priority review voucher (PRV), which J&J used in July 2017 for FDA priority review of a new potential blockbuster drug –

Tremfya – in Janssen’s immunology portfolio. Accelerated approval of bedaquiline, in particular, has drawn the ire of critics of expedited review mechanisms for the FDA, who have been using the mortality imbalance observed during the Phase 2 trial by Diacon et al. as an example of the

FDA lowering its regulatory standards (Avorn, 2013). However, accelerated approval provided some certainty and credibility around the use of bedaquiline and created opportunities to generate supportive, real-world evidence from broader use of the drug outside of clinical trial settings.

Further, the expedited regulatory proces allowed J&J to beat Otsuka to the MDR-TB market. Otsuka’s drug for MDR-TB, delamanid, was hot on bedaquiline’s heels and received

European Medicines Agency (EMA) conditional approval in 2013. Though it is unclear how much of a first-mover advantage bedaquiline gained, since Otsuka has been slower to expand

57 access to delamanid, being able to tout a label like “first new drug in 50 years” generated great excitement for bedaquiline.

The FDA Announcement was widely reported in mainstream media channels, including the Wall Street Journal and the New York Times. Bedaquiline was hailed as a “breakthrough” and “miracle drug” because it presented an alternative to regimens with high toxicity and inadequate efficacy, a potential to shorten treatment, and an option for pre-XDR and XDR-TB patients with strains of TB that were resistant to the existing therapeutic options.

The positive press for bedaquiline came at a time when J&J was facing challenges to its cherished reputation. Though the business’s stock price was healthy, Johnson & Johnson had fallen to 23rd on Fortune’s list of most admired companies after repeated recalls, lawsuits, and investigations (Neff, 2013). Quality problems and recalls of Tylenol and other brands since 2010 led the Food and Drug Administration to mandate manufacturing shutdowns and improvements, while J&J also faced more than 10,000 lawsuits over alleged failures of its Depuy metal-on- metal hip transplants and paid $181 million to settle state lawsuits over off-label marketing of its

Risperdal antipsychotic drug (Neff, 2013). In 2013, J&J VP-Global Corporate Affairs Michael

Sneed provided a glimpse into the company’s long-term reputational positioning by explaining why he was launching a corporate image rebranding campaign to AdAge magazine: “The stakeholders we focus on are so much more varied than they were five or 10 years ago. We certainly have consumers, and they're incredibly important, but we also have a lot of other stakeholders -- doctors, nurses, other health-care workers, regulators, other government officials.

They ultimately make decisions about who they partner with, who they recommend” (Neff,

2013). A different structure was going to have to be put in place to manage a product like

58 bedaquiline that could offer a reputational lift but also expose J&J to criticism from activists if access was not carried out appropriately.

Despite gaining accelerated approval, there were still regulatory hurdles for bedaquiline.

Most importantly, the FDA set time-bound post-marketing requirements to confirm the earlier results or risk losing approval including conducting a confirmatory Phase III trial assessing long- term outcomes of failure, relapse, or death at least six months after all MDR-TB treatment is completed (by 2022), and developing a patient registry to monitor serious adverse events (by

2019) (FDA.gov). Given the exorbitant costs of Phase III trials, and the lengthy follow-up due to the assessment of clinical end points 12 to 24 months after patients complete the multiple-month study-treatment regimen (Cox & Laessig, 2014), a priority for Janssen would be to defray costs.

Further, given the mortality imbalance and lack of additional data on appropriate use, new combinations, and safety, it would be hard to convince regulatory authorities in low- and middle-income countries without additional evidence.

J&J targeted registration first to stringent regulatory authorities, and then countries with high burden. Stringent regulatory authorities, such as the European Medical Authority (EMA), the US FDA, and SwissMedic, are often used as a guidepost for low- and middle-income countries because of their high regulatory standards, and approval here could expedite availability of the drug in other parts of the world where the disease is more prevalent and which use these regulatory authorities’ approvals as references. Approval of bedaquiline by the FDA in

2012 and the EMA in 2014, helped pave the way for registration in other jurisdictions; further,

J&J’s decision to distribute the drug through the GDF allowed for importation of the drug through the use of waivers. However, regulatory mechanisms like the accelerated approval process in the United States and Europe do not have a parallel in most high burden countries, and

59 a combination of the lack of a completed Phase 3 clinical trial, safety concerns from the Phase 2 clinical trial, and strict oversight recommended by WHO has slowed regulatory approval in countries with high burdens of TB.

Treatment and Implementation Guidelines Restrict Use of Bedaquiline

Due to the hierarchical, public sector-run and WHO-led system of tuberculosis control programs, WHO’s recommendations for the introduction and use of bedaquiline were the most important considerations for adoption in low- and middle-income countries. As a result, the adoption of bedaquiline in global and national regulatory standards required J&J to focus on generating clinical evidence that would be considered by the WHO.

Early on, before the FDA approved bedaquiline, the bedaquiline team reached out to

CDC and WHO, priming them for a potential new drug and the need for new or updated TB treatment and control guidelines. In September 2010, the WHO Strategic and Technical

Advisory Group on Tuberculosis recommended that the WHO examine the potential consequences and implications of the introduction of new or repurposed drugs for the treatment of DS and MDR-TB into the market and develop suitable recommendations for their optimal uptake in countries.

Since efficacy and safety data were only available from Phase 2b studies, the guidance was set to be provisional until further efficacy and safety data, particularly from Phase III trial, became available. Within a month after the FDA approved bedaquiline, WHO convened an expert group to assess available data on bedaquiline and issued interim policy guidance on the use of the drug to treat MDR-TB. The US Centers for Disease Control (CDC) also published provisional treatment guidance on the use of the drug. Both recommended reserving bedaquiline

60 for patients with pulmonary MDR-TB when an effective regimen with pyrazinamide and four second-line drugs, as recommended by WHO, cannot be designed (CDC, 2013; WHO, 2013).

Further, WHO recommended bedaquiline’s incorporation into the existing DOTS infrastructure to ensure close supervision. To monitor resistance, systems require drug susceptibility tests or monitoring by serial assessment of minimum inhibitory concentrations of the drug to ensure that resistance does not develop (WHO, 2013). Further, the CDC and WHO both highlighted the need to monitor patients with certain comorbidities, including liver disease given potential hepatoxicity, cardiac disease based on concerns of QTc prolongation (risk of cardiac irregularities), and alcohol and drug abuse.

WHO described five conditions for including bedaquiline in the adult treatment regimen of MDR-TB: (1) Treatment is administered under closely monitored conditions; (2) Proper patient inclusion; (3) Patient informed consent obtained; (4) Adherence to principles of designing a WHO-recommended MDR-TB regimen; and (5) Pharmacovigilance and proper management of adverse drug reactions and prevention of drug-drug interactions. Since the FDA does not require pediatric formulations and testing, bedaquiline was only recommended for adults; a pediatric clinical trial to satisfy EMA approval requirements was in progress at the time of this writing. Current recommendations were limited to adults with pulmonary MDR-TB between the ages of 18 and 65 years, with “caution” exercised in the use of bedaquiline for people who are older or living with HIV. WHO recommended against the use of bedaquiline in pregnant women and children less than 18 years of age, whereas the CDC recommended that it could be considered in these populations and in patients with extrapulmonary disease on a case-by-case basis.

WHO’s requirement for strict pharmacovigilance was understandable, given the limitations of clinical evidence available for bedaquiline. In October 2014, WHO issued a Policy

Implementation Package for New TB Drug Introduction, in which the WHO recommended three prerequisites for the introduction of new or repurposed TB drugs: a national implementation plan for introduction of new TB drugs and/or regimens; monitoring and evaluation of new drugs and regimens, including active pharmacovigilance and drug-resistance surveillance; and a systems approach for ensuring uninterrupted supply of quality-assured drugs.

These complicated pharmacovigilance requirements for new drugs (WHO, 2015b) have been criticized for present a significant barrier for high-burden countries (Furin et al., 2016).

Furin and others (2015) have identified many barriers to the use of new TB drugs, like bedaquiline, under programmatic conditions, including: lack of awareness of drug availability and procurement process; limited technical capacity and expertise; confusion around WHO’s recommendations, especially pharmacovigilance; limited availability of quality clinical trials data supporting the use of new drugs under programmatic conditions; challenges in sharing rapidly changing information about new drugs with key stakeholders and updating guidelines; prolonged turnaround time for drug procurement or import clearance issues; limited access to companion MDR TB medications; and lack of high-level national government support. Among these, the complicated WHO recommendations stand out as a clear deterrent. Along these lines, some advocates for broader use of bedaquiline have judged WHO’s recommendations for the use of bedaquiline to be “conservative” (Stop TB & MSF “Out of Step”, 2017). Mitnick and others

(2008) have repeatedly called out TB community’s “scarcity mentality”, which, out of traditional concern for TB-focused resources, seemingly prioritizes the frugal use of new drugs to avoid antibiotic resistance, over broader use of effective tools to improve treatment of patients,

62 particularly those with MDR-TB. Other researchers and advocates, skeptical of the way in which bedaquiline received accelerated approval, have pointed out the lack of Phase III clinical trial data that could confirm the actual, long-term impact of the drug on clinical outcomes like relapse and death that are only assumed by the use of surrogate endpoints in bedaquiline’s tests (Avorn,

2013). The lack of agreement within the “TB community” about basic policy approaches on when and how to use bedaquiline and other new TB drugs is a symptom of broader disagreements within the world of global TB control about how much to adhere to WHO’s traditional DOTS-focused approach and taking more aggressive steps toward eradicating the disease. Within the broader context of this system, pharmaceutical companies like J&J have significant role to play in bringing new technologies to the world, but must navigate a complex stakeholder environment that leaves companies with limited control, and reliance on creative partnerships, to shape market access strategies for the drugs they create.

Creation of a Global Public Health Organization

J&J’s decision to bring bedaquiline to market itself, rather than sell or donate its rights to the drug, allowed the company to reap longer-term commercial benefits, such as reputational gains, employee satisfaction, and longer-term positioning in emerging markets. However, this decision came with the responsibility to develop a comprehensive market access strategy.

Bedaquiline fit awkwardly in Janssen’s infectious disease productline until a Global

Public Health (GPH) team was developed within, with bedaquiline as its flagship product. GPH was charged with the full clinical development of products and services and for maximizing access to medicines and care for HIV, tuberculosis, hepatitis C, and worm diseases (Janssen website). Notably, Janssen designated GPH as the central point of contact for cooperating with

63 all global public health stakeholders, including governments, non-governmental organizations, and funding organizations (Janssen, 2013). In 2016, the Global Public Health team was moved from Janssen to the Johnson & Johnson enterprise level “Global Public Health Organization”

(JNJ Innovation, 2017). This organization was subsequently elevated to the enterprise level and renamed the Johnson & Johnson Global Public Health Organization (GPH) in 2015. As Jaak

Peeters, head of the Global Public Health Organization was quoted in a press release announcing the change, “The idea is to not only discover and develop products, and make them affordable— but also get traction on how these products will reach and measurably improve the health of the patients that need them. So it made a lot of sense to bring the capabilities and expertise of our consumer, pharmaceutical and medical devices businesses together with philanthropy under a unified, enterprise-wide global public health strategy.”

There were a few advantages of creating a new organization. First, walled-off from competition with other commercially viable products, the GPH team could experiment with new forms of access and partnerships that may not have a sales or profit motive. Successfully creating access to bedaquiline would necessitate a new way of doing business that could accommodate the WHO-driven paradigm and introduce creative approaches to financing and TB advocacy.

Accordingly, the GPH team has been described as a self-sustainable business model focused on cross-sector innovation focusing on resource-poor settings, bridging the core commercial business and J&J’s philanthropy group, Global Community Impact.

Second, successful implementation of new strategies could have a significant reputational benefits, which could accrue to the broader J&J organization. J&J has embraced its leadership role in MDR-TB, with the early success of tools like bedaquiline said to have “renewed industry engagement in TB R&D, pushed countries to develop systems for conducting field trials for

64 policy changes, and revitalized front-line health workers and civil society” (Pai & Schito, 2015;

Furin et al., 2017; Pai & Furin, 2017). In this context, GPH success can be understood in terms of the number of patients treated, employee engagement, strengthened reputation, internal innovation through a new sustainable business model, and how GPH serves as a platform for other products. Finally, this multidisciplinary team would draw from resources across J&J, such as consumer insights, innovation, and government affairs, to support its aim to meet unmet medical needs. GPH was structured to include R&D, market access, and a new operations division with a physical footprint in Africa. The team constructed to help expand access and guide the access strategy for bedaquiline included a range of expertise, including a former assistant TB controller for New York City and an access leader with experience working with vaccines in developing countries.

However, creating a new organization focused on global public health also came with risks, both in terms of internal coordination and, more unpredictably, exposure to external challenges. In a sprawling, matrixed organization like J&J, there is broad latitude to take decentralized risks, but also a cultural emphasis on alignment. Since many of the functionalities of the global public health team touch on existing groups under the J&J umbrella, this new group would need to be very clear about its objectives and boundaries, vis-à-vis other teams and resources in philanthropy and the commercial organization. GPH was still housed within a for- profit enterprise, and operated as a cost center which put it in a risky position; the organization relied upon intangible and long-term benefits like reputation, partnership development, and inroads in emerging markets, which are difficult to measure and evaluate. As a result, it would have to find a way to articulate success based on contradictory pressures from its stakeholders: to

65 become self-sustainable within the broader J&J organization while facing public pressure from the global health community to increase access and lower costs.

The walled-off nature of the organization insulated it from short-term financial pressure, but for long-term sustainability it would need to embed its presence and relevance into the broader organization, including subsidiaries operating in emerging markets. Extensive efforts have been made to embed GPH principles within operating companies in high-burden countries as an opportunity for J&J to “have a different conversation” when meeting with local governments. Initially, he was met with little interest: few local operating company leaders, except in South Africa and India, were enthusiastic about focusing attention on creating access for an unprofitable product and some had concerns about the optics of selling drugs for TB alongside consumer and baby products the company was often known for. Though J&J has continued to limit its distribution channels to its operating companies and established mechanisms like the GDF, these challenges of selling GPH and products like bedaquiline to internal stakeholders highlight a tension and lack of alignment between GPH’s blurred goals of social impact and self-sustainability and the broader company’s for-profit motives.

From its position at the corporate level, GPH’s interface with this complicated external environment also meant that criticism and political dynamics could have broader implications for corporate reputation. In combination with GPH’s purpose to draw positive recognition for the

J&J brand, this has led the team to be highly sensitive to both external praise and criticism.

GPH would have to learn to operate in different environments and with a complex array of stakeholders in the long-established TB community. Given the extensive history of the disease, there were complicated political issues characteristic of TB but which required careful navigation on multiple levels. For example, leadership of the WHO’s TB portfolio would be key

66 stakeholders to engage in legitimizing TB control and treatment decisions in countries, but had a comparatively conservative approach, while varying levels of advocacy from civil society members were eager for new tools and departures from the WHO-recommended DOTS- dominant TB control strategy. The established authority of public sector national TB programs also indicated that these would be key in-country stakeholders, though this would not necessarily facilitate use of bedaquiline in those high-burden countries characterized by widespread use of private sector health care services. The proliferation of additional institutions and civil society members with voice and influence on the global health stage, and few established venues for industry participation or policy influence, indicated that the company would need to influence through networks and various partnerships.

Fortunately, given the limited and concentrated global health sources of TB funding originating from the United States, J&J was well-positioned to leverage its status as a major

American company, with dual roles as an engine for economic growth and provider of health care solutions. However, for a company with few drugs targeting developing countries, J&J would, at the very least, learn a lot about systems in the complex global health arena and in a broad swath of developing countries where J&J had no, or limited, operational presence.

Limited Uptake of a “Miracle Drug”

In bringing bedaquiline to market, J&J was set to encounter the very challenges that often serve as deterrents to investment in the first place. By the end of 2017, 103 countries had access to bedaquiline, including 29 of the 30 countries with high MDR-TB burdens (AtMI, 2018).

However, these statistics refer to countries that have had at least one person use the medicine through compassionate use and offers only a top-line view of actual access. Programmatic data

67 has suggested that as of October 1, 2017, there were 12,194 patients on bedaquiline, most of whom (7,500 patients) have been treated in South Africa (DR-TB STAT, 2017). The overwhelming concentration of bedaquiline use in South Africa invites exploration into why such efforts have focused on South Africa. Further, though almost 2,000 more orders than tracked in programmatic use had been ordered from the GDF (DR-TB STAT, 2017), less than half of 30,000 courses of bedaquiline that J&J decided to donate through USAID have been distributed. This demonstrates that price is not the primary barrier for access to bedaquiline, and that there are other barriers to uptake of products that are free, quality-assured, and distributed through an established system. Clearly, the actual demand for the drug among donation-eligible countries and scope of use has been limited (DR-TB STAT, 2017): most countries are either not using the new drugs or the utilization has focused only on small pilot projects (Pai & Furin,

2017).

Three Strategic Challenges to Making Bedaquiline Accessible

There is little consensus around a definition of access to medicines in pharmaceutical systems. The term access is most commonly understood as availability, affordability,

(geographical) accessibility, and (cultural) acceptability of quality products and services (SIAPS

Partners’ Consultative Meeting, 2014). One guide for understanding access in TB drugs comes from the TB Alliance’s three-point approach articulated in the organization’s mission as “the

AAA mandate.” According to the AAA mandate, the TB Alliance aims to ensure that all new products it develops will be adopted by global, national, and local regulatory bodies, reach those in need, and be affordable to those with TB and health systems. This simple three-part framework - adoption, availability, and affordability - was used by Frost and Reich (2008) to

68 describe health systems reform in the pharmaceutical sector, with the addition of a fourth “A”, architecture, to describe decision-making capacity. For the purposes of this case study, which takes the perspective of a pharmaceutical company, I have used the AAA framework as a practice-based model by which to organize and understand the strategies and challenges that J&J has deployed and faced in each of these three domains.

Improving Adoption despite Knowledge Gaps

It will be difficult for practitioners and program managers implementing the drug to make well-informed decisions without additional research to fill in knowledge gaps about issues such as optimal regimens and treatment duration, interactions with other standard TB medicines, and anti-retroviral therapies, and safety and effectiveness in key populations, such as pregnant women, children, and people living with HIV/AIDS (Stop TB & MSF, 2017).

Tepid Adoption by Key Regulatory Authorities

Three years after WHO issued its first set of interim policy guidance for the use of bedaquiline in 2013, the organization convened a Guidelines Development Group to reevaluate additional evidence gathered from bedaquiline’s introduction in over 70 countries at that point.

Ultimately, the group decided to uphold the recommendation set in the initial interim guidance for two main reasons. First, the majority of evidence collected arose from observational studies, which is not “sufficiently strong” to recommend that bedaquiline be used for all MDR-TB patients. Second, given a new WHO recommendation earlier that year for the use of a shorter regimen, also known as the Bangladesh regimen, maintaining the initial guidelines would restrict bedaquiline to the sub-set of patients who are not eligible for the newly recommended shorter

69 regimen (i.e. MDR-TB with additional resistance or intolerance to fluoroquinolones and second- line injectable drugs).

The first issue highlights the importance of completing the requisite Phase 3 clinical trials mandated of bedaquiline by the FDA. J&J has received some criticism over the delayed initiation of its Phase 3 trials, leading to some speculation that the company was banking on use of observational, real-world evidence to establish its safety and efficacy record. Since most post- approval studies required of the FDA are not actually completed (Woloshin et al., 2017), it would not be out of the ordinary if J&J did not finish its Phase 3 study. Further, there is a risk of disenchantment with bedaquiline if the Phase 3 study does not yield favorable results. In 2017, the Phase 3 clinical trial of delamanid was completed, but failed to demonstrate “superiority” over lengthier standard of care; while some observers suggest that outcomes were close enough, and the benefits of an additional mechanism of action against tuberculosis warrant continued use of delamanid, these results were highly disappointing for the vast expense and effort the trials require. Unlike bedaquiline, delamanid has been rolled out and used in far fewer patients, so the

Otsuka lacked substantial programmatic data to contextualize the Phase 3 trial results. This emphasizes challenges in TB control, and the need for continued investigation of both individual drugs and combination regimens (TAG Webinar, 2017). It also validates J&J’s approach, however insufficient to change WHO guidelines, to develop robust observational, real-world evidence to support programmatic use of bedaquiline. In the absence of a Phase 3 trial, early access programs and strong programmatic evidence from bedaquiline use in over 8,000 patients

(Pai & Furin, 2017) have convinced civil society activists of the merits of bedaquiline, over current MDR-TB regimens (GTBCAB/Low et al., 2018). The WHO’s decision not to recommend bedaquiline for the full breadth of the MDR-TB population, however, signaled

70 dissatisfaction with comparatively weak evidence, and put pressure on the company to initiate its trials in a timely manner. This trial will be critical to demonstrate to national and local regulatory authorities that bedaquiline is indeed safe and efficacious.

The second issue highlights the rapidly changing nature of TB guidance. In 2016, WHO updated its recommendation for MDR-TB treatment, adopting the so-called “Bangladesh regimen” that would dramatically shorten and lower the cost of the MDR-TB treatment regimen.

Though this regimen was based primarily on observational data, the value of this improvement was recognized as a significant advancement. However, in 2017, a clinical trial (called STREAM

Stage 1) testing the shortened treatment regimen for MDR-TB failed to demonstrate “non- inferiority” over the former standard of care. Stage I of the STREAM trial (a phase III study conducted by the Union comparing a 9-12 month standardized regimen to 18-24 months of individualized treatment for MDR-TB, both of which are recommended by the WHO under certain conditions) have also created uncertainty regarding the optimal treatment for MDR-TB based on existing evidence. The STREAM trial did not show that the new shorter regimen is non-inferior to the previous 18–24 month standard of care for MDR-TB (Rusen et al., 2017).

Under the conditions of a randomized, controlled clinical trial (RCT), both regimens achieved around 80 percent treatment success. While the shorter regimen performed similarly in the RCT

(78 percent treatment success) to previously conducted cohort studies (Trebucq et al., 2017), the control (the 18-24 month regimen) performed better in the RCT than commonly reported in program settings (80.6 vs. 54 percent treatment success). While WHO is continuing to endorse the shortened regimen, some might argue that the Bangladesh regimen’s heavy reliance on toxic second-line drugs remains problematic, and new drugs are still needed.

In fact, In a February 2018 letter to the WHO Director-General, the Global TB

Community Advisory Board, a body representing key civil society stakeholders, disseminated a position statement demanding that “The World Health Organization (WHO) must recommend bedaquiline as part of the preferred regimen for multidrug-resistant tuberculosis (MDR-TB)” in the face of growing evidence of the drawbacks of second-line injectables and merits of third-line bedaquiline. According to WHO guidelines (2016), people with MDR-TB should receive an injectable unless they are tested for and show resistance or signs of hearing loss, in which case they may qualify for treatment with bedaquiline (WHO Interim Guidelines for BDQ, 2013).

Aminoglycosides, or injectable agents, cause hearing loss in as many as half of patients (Shin et al., 2007; Torun et al., 2005); these include amikacin, capreomycin, and kanamycin. However, few patients are actually screened for hearing loss, since audiometry is not frequently implemented. Further, a review of injectables, referring to them as “the devil we know,” observed that there were no RCTs evaluating their use, and despite almost 20 years of recommended use, evidence of their efficacy was “weak at best” (Reuter et al., 2017).

In contrast, accumulating evidence suggests that bedaquiline is effective against MDR-

TB, including as a substitute for the injectable agent (WHO Report of the Guideline

Development Group, 2016).

Partnering to Close Knowledge Gaps

Broader adoption is facilitated by the growing body of evidence supporting the use of bedaquiline and closing knowledge gaps that deter countries from approving bedaquiline.

Ongoing and recently initiated Phase III and pediatric trials, non-profit-led observational studies, as well as trials that looked at combining bedaquiline with other new drugs and in shorter regimens have all supported the case for bedaquiline’s efficacy and safety.

Like all drugs for TB, bedaquiline must be used in combination with other drugs to maximize efficacy and prevent resistance. However, bedaquiline’s clinical trials were conducted by tacking the experimental drug onto the standard-of-care, rather than combining bedaquiline with other new compounds to develop novel combination regimens. Through J&J’s partnerships with the TB Alliance, bedaquiline has become a potential cornerstone for testing optimal combination regimens. TB Alliance’s Nix-TB trial is the first clinical trial to test a new, all-oral regimen for extensively drug-resistant TB (TB Pipeline Report, 2017). All surviving patients were culture negative at four months—74% were already negative at eight weeks, remarkable results considering previous outcomes for XDR-TB have low cure rates and high mortality (73% at five years, higher in people with HIV) (TB Pipeline Report 2017). These studies are building an important evidence base to support broader utilization of bedaquiline.

Multi-partner models, supported by multiple funding sources, have become the dominant strategy for managing the high costs of Phase III trials (Rosenblatt, 2017), which have been called “the single greatest challenge” that large pharmaceutical companies face (IOM

“Roundtable on Value and Science-Driven Health Care”, 2013; Getz, 2014). On Nov. 6, 2014,

Janssen Research & Development announced a collaboration with USAID, the International

Union Against Tuberculosis and Lung Disease (The Union), and other partners to include bedaquiline in the STREAM study, an ongoing, multi-center international randomized controlled trial to evaluate a standardized treatment regimen for MDR-TB. The second stage of this study will include two bedaquiline-containing treatment arms to further assess safety and efficacy in

73 adult patients with pulmonary MDR-TB and also to evaluate a new treatment regimen, including an all-oral option (Janssen PR, 2014). This trial will qualify as part of post-approval requirements for bedaquiline from both the FDA and the EMA as an alternative to the initially planned Phase 3 trial of bedaquiline.

Balancing Availability with Stewardship

As for all antibiotics, making bedaquiline widely available in the public and private sectors must be balanced with stewardship for appropriate use to avoid antimicrobial resistance.

Accordingly, J&J has relied upon highly regulated, public sector programs and delivery mechanisms to facilitate availability of the drug.

Compassionate Use Cultivates Local Allies

Before regulatory approval, access to investigational drugs and biologics can be granted through “compassionate use” and “expanded access” programs (FDA), compliant and controlled mechanisms of access to investigational drugs outside of formal clinical trials and before the commercial launch of a drug (Patil, 2016). In 2011, Janssen initiated a compassionate use program, while the drug was in phase II-B trials. Approximately 700 patients had accessed bedaquiline through compassionate use by the time this program had ended in 2015 (MSF, 2016) with the launch of the Bedaquiline Donation Program through USAID. Pharmaceutical companies are increasingly adopting early access programs due to several benefits. Companies can develop positive relationships with key opinion leaders, patients, advocacy groups and regulators, who may use their experience to support the drug to regulatory agencies, and collect feedback from early adopters and patients (Pharma Letter, 2008; Patil, 2016). Further, companies can use the data captured from the implementation of expanded access programs to support

74 global commercialization strategies, particularly to enhance market penetration through increased acceptance and uptake prior to commercial launch of a product (Patil, 2016). For a drug like bedaquiline that is not expected to be profitable, expanded access is also more economical than seeking full-scale regulatory approval for the countries or regions (Simon,

2010).

J&J’s Compassionate Use Program provides a pressure valve for bedaquiline demand that is restricted by slow or restrictive national approval and access policies. For example, in

India, the National Tuberculosis Program's (RNTCP) insistence on reserving bedaquiline for patients who have at least three susceptible drugs in the background regimen has limited use of the drug for advanced resistance. The head of a private clinic in Mumbai, Zarir Udwadia has successfully procured bedaquiline for 33 of 40 of patients with advanced resistance (XDR and beyond) (Udwadia et al., 2017). However, the compassionate use application process is still

“tedious and onerous”, involving an online application, individual case review by J&J, application for the import permit, dispatch, shipping, and customs clearance; Udwadia and colleagues estimate that it takes an average of 49 days from the time of application to its receipt, while in three cases, the drug was “interminably” held at Indian customs. Therefore, while compassionate use provides an option for pre-approval access, it can still be a slow process with damaging delays for the patients who need treatment options the most.

Availability Facilitated by Centralized Procurement

Janssen holds the product patent for bedaquiline, meaning production can be carried out by Janssen, a producer that is licensed by the patent holder, or by generic producers if the technology is no longer on patent (or is not patented in the country). Janssen has a licensing

75 agreement with Dishman Pharmaceuticals and Chemicals Ltd., a leading global manufacturer of pharmaceutical active ingredients, to secure the active pharmaceutical ingredient for bedaquiline

(Reynolds, 2015). When greater numbers of patients are reached worldwide in the future,

Janssen may look to engage with other global partners for production and/or marketing.

GPH has only licensed selectively to key partners. In addition to the TB Alliance, bedaquiline is licensed to Pharmstandard, a large pharmaceutical company based in Russia.

Under a licensing agreement signed in 2012 and initiated in 2013, Janssen granted commercial rights for bedaquiline to Pharmstandard to use in the treatment of MDR-TB in the Russian

Federation and a number of other countries in the region1. Janssen also transferred certain technology and production know-how for bedaquiline to Pharmstandard (Janssen PR, 2012).

That year, Pharmstandard became the Marketing Authorization Holder for bedaquiline in Russia, meaning the company also holds responsibility for obtaining state registration and liaison with regulators and health authorities to ensure market access and availability of the drug (Janssen

PR, 2012).

Leveraging Consolidated Supply Chain Infrastructure through the Global Drug Facility

In many LMICs, bedaquiline is made available through the Global Drug Facility (GDF).

As described earlier, the GDF was established in 2001 as a mechanism to expand access to, and availability of, quality-assured anti-TB drugs and diagnostics through pooled procurement

(Kumaresan, Smith, & Evans, 2004). The GDF’s Quality Assurance policy deems all products that are included on the WHO List of Prequalified Medicinal Products and approved by a stringent regulatory authority, or temporarily by the Expert Review Panel, eligible for

* Per the licensing agreement, Pharmastandard’s territory includes Armenia, Azerbaijan, Belarus, Georgia, Kyrgyzstan, Kazakhstan, Moldova, The Russian Federation, Tajikistan, Turkmenistan, Ukraine and Uzbekistan. 76 procurement (Stop TB Partnership “GDF”, 2017). The GDF is a “one-stop shop” for national TB programs procuring their TB drugs, and it is the largest supplier of quality-assured patient treatments worldwide in the public sector. A major advantage is that even countries without prior approval or registration could procure drugs through the GDF by using a waiver process.

Alternatively, for selected middle- and high-income countries, bedaquiline is also supplied through the local Janssen affiliate directly to the Ministry of Health (or designated purchasing entities) (MSF, 2016). Partnership with the GDF has taken care of most forecasting, procurement, distribution, and delivery concerns for J&J, though fundamental weaknesses in the second-line global supply chain and lack of procurement mechanisms for bedaquiline in the private sector present potential challenges to scaling up access to the drug.

Continuing Challenges with Availability of TB Products

However, key issues still remain. First, supply shortages and higher prices for raw materials, provided by few suppliers, have led to inconsistent supply of TB treatments, creating a risk for the development of resistance. Second, new and more expensive second-line drugs that would be companion drugs for bedaquiline are not always procured through the GDF.

Navigating the small and ambiguous market for second-line TB drugs, in particular, presents specific forecasting challenges due to the diverse and often changing regimens to treat MDR-TB patients. This means that many second-line drug manufacturers rely on “make-to-order” production, starting production, and even procurement of the active pharmaceutical ingredient, only after receiving final purchase orders (Yadav/NASEM, 2012); it can take up to 36 weeks to procure second-line drugs (Yadav/NASEM, 2012), a delay that is often blamed on manufacturers and raises a risk of inconsistent supply of companion drugs. Further, WHO has noted that “it is

77 difficult to find suppliers willing to spend the funds to prequalify their products according to the international quality assurance policies, or even to register these medicines in several countries”

(WHO Companion Handbook, 2014). Since most drugs used in WHO-recommended treatment regimens are generics, most public-sector purchasers prefer to purchase TB drugs directly from domestic manufacturers and not from the global marketplace, unless there is a donor-based requirement to procure through the GDF (TB Alliance, 2007), as is the case with the USAID

Bedaquiline Donation Program.

Third, GDF lacks a formal mechanism to forecast aggregate demand for all TB products, since the GDF only calculates need within public-sector DOTS programs (CGD, 2007). This last point highlights the lack of connectivity with private sector providers, with WHO calling for a ban on over-the-counter sales of TB medicines (WHO, 2014). WHO’s concern is that TB medicines dispensed over-the-counter in the private sector may facilitate drug resistance: people may seek treatment directly from a pharmacy, where staff are untrained, and necessary medicines may be unavailable or of poor quality, and people may not receive recommended, quality-assured medicines and/or regimens for their TB (WHO, 2014). However, in many parts of the world, the private sector is the primary provider of TB drugs and care, which severely limits access to life-saving treatments.

Unfortunately, availability also depends on local supply chains, not only for bedaquiline but also for companion drugs. Though bedaquiline is primarily available in highly monitored settings today, in the future, reliance on combination therapies exposes patients receiving bedaquiline-containing treatments to shortages of tuberculosis drugs have been tracked around the world, including the US, since their development. Even the US experiences shortages of key medications and cost escalations in first- and second-line TB medications (Centers for Disease

Control, 1991; Marwick, 1992; Scott et al., 2015). Weak systems for procurement and supply chain management have led to poor quality drugs and treatment interruptions and contributed to the rise of MDR-TB (Raviglione et al., 2001).

Even though nearly all countries have introduced DOTS as modules within national health-information systems, with standardized and routine quarterly reporting, district-based registers, and patient cards held by facilities to track cases (Atun et al., 2010), local capacity to collect and use data from routine data systems remains weak. National TB programs typically calculate estimates of impact from ineffective tuberculosis registration and reporting systems, small cohort surveys of tuberculosis prevalence, and annual surveys on the risk of tuberculosis in school-aged children in high-TB prevalence areas (Atun et al., 2010). Growing caseloads of patients with TB and HIV infection, larger cohorts of patients needing retreatment, including for

MDR-TB, as well as the large role of private providers, has created additional challenges to assessing prevalence and the effect of interventions (Atun et al., 2010).

Another major challenge of increasing access to bedaquiline is the drug’s general inaccessibility to the private health care sector. Many countries with high burdens of TB, like

India and the Philippines, have large private health care sectors that account for significant portions of TB drug sales and TB care but presents challenges to National TB Program-led control for several reasons. First, patients may not be reported into the national TB control program, complicating estimates of TB burden, diagnosis, and treatment. Second, public procurement of quality-assured drugs are often inaccessible to the private sector. Third, physicians may prescribe non-standard regimens, with less focus on treatment adherence.

Increasing use of community health workers and approaches to integrating private sector and

NGO providers into a “public-private mix” have supported tuberculosis control efforts (Atun et al., 2010), but complicate questions about access and stewardship.

Managing Affordability alongside GPH Self-sustainability

With a novel drug like bedaquiline, the Janssen team knew that they were experimenting.

Janssen’s basic approach to pricing medicines includes: considerations of value (clinical benefits vs. standard of care, unmet need, patient experience, economic impact); access and affordability

(broad and timely access, budget impact, leadership); and incentive for innovation (development cost, business risk, profit), taking into account the variety of payment and provider models present across different countries (payers, governments, healthcare providers, NGOs) (Janssen website).

The value of bedaquiline to patients and society is arguably high, based on the efficacy and growing evidence of safety of the drug, particularly when compared with the current standard of care (WHO, 2016). Quality of life and patient satisfaction with treatment (measured for bedaquiline) is supported with the potential emergence of shorter treatment regimens with fewer damaging side effects, like permanent hearing loss. Further, cost-effectiveness analyses have established that bedaquiline performs well on economic analyses of total cost of care, disability and productivity, and benefits to society.

An early, conservative estimate used by the WHO Expert Committee devising the first set of treatment guidelines estimating cost per DALY indicated that adding a 24-week regimen of bedaquiline to the current practice of MDR-TB treatment would be relatively cost-effective in most settings. Results, though, were ambiguous in low-income (lower willingness-to-pay)

80 settings and highly dependent on the assumptions made about the generalizability of trial results to cost effectiveness in routine settings (Vassell, 2013).

Access and affordability for bedaquiline is a particular challenge, given that high-burden countries are overwhelmingly low- and middle-income, have a range of social protection and financing schemes, and may not cover second-line drugs. A variety of tools and approaches are generally available to pharmaceutical companies when navigating list prices and the prices patients face, such as tiered pricing, discounted prices and rebates, product donations, coupons to help patients cover co-pays, and sharing intellectual property to enable other manufacturers to produce and sell patented medicines. While specific strategy has varied by market, Janssen has instituted a tiered pricing scheme and a four-year Bedaquiline Donation Program for qualifying countries (2015-19).

Shifting from Tiered Pricing to Donations

Given GPH’s role in between corporate philanthropy and the traditional commercial business model, GPH has strived to develop a sustainable business model. Reflecting the fundamental tension, and indecision, between generating a sufficient profit to recoup R&D costs and sustain further R&D and ensuring that drugs are affordable to patients and health systems,

GPH has implemented both a tiered pricing strategy and a time-bound donation program.

Janssen has implemented a three-tiered pricing framework that attempted to balance a country’s ability to pay with the burden of disease for countries that are not eligible for Global

Fund grants. Tiered pricing is a form of price discrimination, in which Janssen aims to obtain a larger volume of sales at low profit margins in the poorest countries, offset by higher-priced sales in middle-income countries, and purely monopoly-priced revenues in countries without price

81 controls, such as Medicare and private insurance markets in the United States (Danzon & Towse,

2003; Outterson & Kesselheim, 2008). Theoretically, price discrimination that sets product prices closer to a consumer's willingness or ability to pay can increase consumer welfare by enabling people who need the product but previously were unable to afford them to afford them, while allowing Janssen to avoid selling below cost.

Janssen has published its “equity-based tiered pricing framework” strategy publicly

(Daems et al., 2013), in which the cost is calculated based on each country’s economic condition and disease burden. The pricing for the middle and lower pricing tiers is aligned with a WHO- sponsored cost-effectiveness assessment of bedaquiline (Vassell, 2013): for a 6-month course of bedaquiline, the price for high-income countries is $30,000, $3,000 for middle-income countries, and $900 for resource-limited countries; for comparison, in 2015, the price of Otsuka’s novel drug delamanid was $33,000 in Japan (MSF Access Campaign, 2015). J&J hoped to use this transparent pricing rubric as further leverage to demonstrate goodwill, as use of tiered pricing for vaccines has been described as a “win-win-win situation” for producers and consumers in high- price and low-priced markets (Plahte, 2005); other large pharmaceutical manufacturers, even of generically available medicines, have not made their pricing strategy public (MSF, 2016).

Advocates criticized J&J for its pricing framework, given that new drugs must be used in combination with a treatment regimen that already costs between US$1,800 to $5,000 per treatment course (MSF Access Campaign, 2015). This criticism focused on high prices particularly for middle-income countries that have or are transitioning away from Global Fund and other international funding sources, as well as the perceived contradiction of assigning high prices to drugs that have benefitted from government incentives (Sanjuan & Malpani, 2014).

There are also some concerns about affordability of bedaquiline for individual patients since few

82 governments provide drugs for MDR-TB – unlike for first-line TB drugs – universally and countries have varying levels of social protection. Though many National Tuberculosis Programs provide first-line tuberculosis drugs at no out-of-pocket cost to patients, only some cover 2nd line drugs, which are orders of magnitude more expensive and difficult to predict given the need for customized combination regimens (TB Alliance, 2007). High variance in available and dedicated funding for MDR-TB treatment across settings complicates the issue. Funding for TB care and prevention reached $6.9 billion in 2017, 84% of which was provided from domestic sources

(WHO, 2017). However, the source of financing varies widely by country. In Brazil, the Russian

Federation, India, China and South Africa (BRICS), which collectively account for almost half of the world’s TB cases, domestic funding dominates (WHO TB Report, 2017). However, in lower-income countries and most of the 25 high-TB burden countries aside from the BRICS, international donor funding remains crucial and exceeds domestic funding (WHO TB Report,

2017). However, health systems across income brackets have been increasingly focused on containing costs of health care, despite the need in most countries to expand domestic budgets for MDR-TB treatment.

An assessment of patient costs in seeking care for drug-resistant TB in South Africa found that despite free health care, patients actually faced high costs (Ramma et al., 2015), highlighting the interrelationship between health systems and social protection challenges.

Though 26 of the 30 high-TB burden countries have a policy document, strategy or legislation for social protection, actual protection is fragmented, highlighting the need for integrated efforts to achieve poverty alleviation and universal health coverage (WHO TB Report, 2017). High- income countries generally provide treatment for MDR-TB patients as an integrated component of the general healthcare system; in the US, this involves a mix of public and private payers, with

83 patient assistance from pharmaceutical manufacturers for the uninsured (TB Alliance, 2007).

Clearly, at the time that the pricing structure was set, its designers did not anticipate the vociferous criticism the tiered pricing strategy would attract (MSF, 2013; MSF, 2015).

In response to this criticism, and shortly after issuing its tiered pricing framework,

Janssen announced a Memorandum of Understanding with the United States Agency for

International Development (USAID) in 2014. The Bedaquiline Donation Program included a four-year commitment by Janssen to donate an estimated $30 million worth of bedaquiline, translating into approximately 30,000 treatment courses to more than 100 Global Fund to Fight

AIDS, Tuberculosis and Malaria (GFATM)-eligible low- and middle-income countries through the GDF (USAID, 2015). Beginning on April 1, 2015, bedaquiline ordered through the GDF was free for countries eligible for the Janssen donation (eligible countries are Global Fund-eligible countries for TB grants), though this excluded South Africa and capped donations to countries in the Commonwealth of Independent States (CIS). Though “donation” is in the title, GPH did not view the Bedaquiline Donation Program as a charity-based endeavor. Rather, a benefit of this program was the ability to collect additional data and insights into real world use of the drug in a cost-effective manner. To support WHO’s implementation and pharmacovigilance requirements,

Janssen has also been able to leverage USAID’s on-the-ground resources and technical assistance in many countries where J&J does not have a presence.

Despite the attempt to remedy criticism over its pricing strategy with a donation program,

J&J has received criticism from the MSF Access Campaign for relying on donations to distribute the drug. MSF has suggested that instead of donating the drug, J&J could offer their license to companies that could place this drug “at the center of their commercial operations and not on the periphery” (Delaunay, 2016), such as by donating its patent to the Medicines Patent Pool to

84 allow generic manufacturers to license bedaquiline for a fee and produce lower-cost generics.

Janssen’s access leaders would agree that donation programs are generally not sustainable, but licensing to generic manufacturers, which are volume-driven, could violate stewardship concerns. Further, the fact that only a fraction of donated drugs have been requested by eligible countries, thereby removing the price barrier, has demonstrated that lack of health system demand and capacity, rather than price, is driving slow uptake.

In this context of financial pressure for national TB programs, affordability quickly becomes a highly political issue that raises the risk and possibility of strong action from governments. Reich (2000) has written that there are three ways to ensure access of drugs: market, munificence, and mandate. J&J has attempted to use a combination of the first two through its voluntary pricing strategy and donation program, though it has resisted donating patent rights. Of the three, a government mandate to lower prices or relinquish a patent would be a worst-case scenario. In particular, health activists have advocated for the broader use of legal mandates allowed under the Trade-Related Aspects of Intellectual Property Rights (TRIPS)

Agreement: through compulsory licensing, a country’s government could enable a local company without the patent to manufacture drugs within the country under certain conditions; through parallel imports, a country could purchase new drugs from parties in countries where the price is low in order to lower prices (Reich, 2000).

J&J has long identified that selling medicines internationally exposes it to international and national rules and regulations, which can put its intellectual property at risk (J&J Annual

Report, 2017). One recent example has emerged in India, where in January 2017, an MDR-TB patient in India successfully sued the Indian government after being denied access to bedaquiline. This woman, who became known as the “Patna patient”, put a spotlight on the

85 human cost of restricted access to the medicine. Once the Bedaquiline Donation Program ends in

April 2019, bedaquiline would cost $900 per course, per Johnson & Johnson’s tiered pricing strategy (Lawyers Collective, 2018) Advocates for greater bedaquiline published a letter to

Indian Prime Minister Narendra Modi in March 2018, asking him to allow generic companies to legally produce cheaper versions of the drug (Bhuyan, 2018; Lawyers Collective, 2018) by using compulsory licensing; the 60 signatories believe that compulsory licensing would lower the price of bedaquiline in India by up to 95%, with modelled estimates pricing generic versions of bedaquiline at $8-$17 per month (Gotham et al., 2017; Lawyers Collective, 2018). The government and J&J subsequently entered negotiations on price, with J&J reportedly offering to provide a discount: one course free for every four courses purchased at $900 each (Raghavan,

2018). However, pressure for lower prices is not likely to abate, and may embolden other countries to consider using this mechanism, though this would put an additional damper on TB innovation from private pharmaceutical companies.

South Africa: An Example of Bedaquiline Access

Today, over 60% of bedaquiline used worldwide is used in South Africa, making it an important example for understanding how bedaquiline can be made more available in high- burden countries.

South Africa is on the WHO’s high-burden country lists for TB, HIV-TB co-infection, and MDR-TB. South Africa has one of the highest numbers of incident TB cases relative to its population size: in 2016, over 500 people per 100,000 population had TB (WHO, 2017).

However, it also has a relatively robust TB and HIV health care infrastructure, and nearly half of all people who newly enrolled in HIV care started on TB preventive treatment were in South

Africa. Further and some of the highest levels of domestic financing of TB of a high-burden country (WHO, 2017). The story of how South Africa transitioned from a compassionate use program, in which J&J granted qualifying individuals with access to bedaquiline during the clinical development process, to a systematized, country-led “Clinical Access Program”, and ultimately to fast-tracked approval of the drug is a story of the success of bedaquiline. On one hand, from J&J’s perspective, the series of events that took place in South Africa provide an exemplar model for diffusion of innovation, and one that may be replicated as a form of accelerated approval in other developing countries. Prominent advocates within South Africa may agree, particularly given the high prevalence of drug-resistant TB, including outbreaks of

XDR-TB for whom few options are available. On the other hand, those who may be concerned about the integrity of the regulatory approval process, which is designed to protect consumers from potentially dangerous or ineffective medicines, may have some reservations.

The Republic of South Africa created a Clinical Access Program for bedaquiline

(Conradie et al., 2014), with the goal to provide the drug to patients with pre-XDR-TB or XDR-

TB, which was then used to make the case for fast-track approval of the drug. The country’s expansion of bedaquiline, as well as the implementation of GeneXpert, is often credited to the political will of Aaron Motsoaledi, South Africa’s Minister of Health who is also the Chair of the

Stop TB Partnership’s Coordinating Board and the Chair of the Global TB Caucus of parliamentarians pushing for TB legislation. While Motsoaledi’s role and top-down approach is most often told and his high-level leadership celebrated, South Africa’s Clinical Access Program was also enabled by grassroots activists who have been able to see and experience the benefits of bedaquiline, and lobby for its expanded use and generate enthusiasm from academics, providers, and patients across the country. J&J’s compassionate use program served to “show not tell”

87 bedaquiline’s benefits, letting evidence of bedaquiline’s efficacy, particularly among populations with few treatment options, to speak for itself.

The first recipient of TMC207 through this compassionate use program was a doctor from South Africa who had multi-drug resistant tuberculosis. Dr. Dalene von Delft, who was slowly losing her hearing as a result of toxic second-line MDR-TB drugs, was one of four patients with MDR whom researchers doing TB prevention trials proposed for special compassionate use of bedaquiline (Bateman, 2013). Von Delft was cured – and emerged from the experience an activist clinician, urged by advocates at the Treatment Action Group and

Medecins Sans Frontieres to go public with her experience (Bateman, 2013). She travelled to present at lung health conferences around the world, including a presentation at a Janssen leadership summit to make another appeal for more TB drugs (Bateman, 2013). In those early days of bedaquiline development, Janssen access leaders have mentioned that it helped having a high-profile, voluntary spokesperson like Von Delft, who presented an unconventional face of

MDR-TB and a hopeful testimonial, creating public pressure for access to bedaquiline.

The South African government decided to develop a structured program by which to roll out and monitor bedaquiline in a more formal manner. In March 2013, the Medicines Control

Council of South Africa, the country’s drug regulatory agency, approved a national Clinical

Access Program, which would incorporate systematized safety monitoring and additional guidelines to treat selected drug-resistant TB patients with bedaquiline. In this model, which was supported by the National Department of Health, Right to Care (a USAID-funded NGO) and

Médecins Sans Frontières, a clinician requested a drug for a named individual patient based on a specific clinical access guidance document; patients could be enrolled and offered access to the medication if they met specific eligibility criteria.

The program outlined four goals: to protect patients; to minimize the risk of treatment failure and emergence of resistance; to exercise fairness; and to comply with regulatory guidance

(Conradie et al., 2015). The plan ensured that at least one clinical site would be available in each province, though initial sites were selected to begin the access program based on clinical research capacity. To protect patients in the face of a potential safety risk of Qtc interval prolongation, the access program built in rigorous electrocardiogram monitoring, with only sites with capacity to adhere to this allowed to enroll patients. Participating patients were required to be treated by the national TB program to improve monitoring and availability of other quality- assured and approved second-line TB drugs. Finally, to minimize the risk of treatment failure, a

South African clinical advisory committee of experts in MDR- and XDR-TB was formed to ensure that bedaquiline is never added to a failing regimen and suggest an optimal treatment regimen for each case (Conradie et al., 2015). This additional infrastructure strengthened the

South African government’s faith in the oversight of the clinical access program, and met WHO recommendations for pharmacovigilance of new bedaquiline patients. Further, clinical approval was coordinated with a Janssen Global Program Manager, based on a panel of clinical experts, and communicated back to each site (Conradie et al., 2015).

The South African government used the clinical access program to collect additional safety data, per MCC standards, and push for fast-track approval of bedaquiline (Health-e News

Service, 2014). In October 2014, the MCC approved the use of bedaquiline for the treatment of

MDR-TB, and in June 2015, South Africa issued a policy framework for the introduction of new drugs and drug regimens for the management of drug-resistant tuberculosis in South Africa, based on this “phased” approach to bedaquiline introduction. In addition to bedaquiline, this approach has been used to introduce other new anti-TB drugs, such as delamanid.

South Africa’s compassionate use program, which, with added infrastructure and country-level ownership became a “clinical access program”, has created a model to increase availability of bedaquiline, beginning with an expanded access program and progressing to accelerated approval after specified clinical standards are met. This regulatory model has been emulated for other experimental TB drugs in South Africa, and also used in India, where data collected from a compassionate use program was used to inform drug approval.

J&J supported the roll-out of bedaquiline in South Africa through strong affiliations with

South African organizations. Underscoring the company’s commitment to supporting TB control in South Africa and other countries on the continent, J&J opened an office in Cape Town in

2016. J&J has supported the clinical access program by enhancing access and treatment, advocacy, and education and prevention through partnerships with the public sector and NGOs like FiND. For example, J&J has worked with partners to provide portable audiometers to monitor for hearing loss, an irreversible side effects of injectable second-line drugs that also serves as proof of regimen toxicity warranting replacement with bedaquiline. Further, through health care worker training, antibacterial surveillance, and support of an MDR-TB registry, J&J has focused on building the health systems capacity to introduce and scale bedaquiline.

Part V: Discussion on Lessons from the Bedaquiline Case

Given pharmaceutical companies’ historical reluctance to invest in neglected diseases like TB, the prospect of a drug like bedaquiline was unlikely. Indeed, the story of J&J’s decisions around bedaquiline offer implications for the J&J’s current organization of its TB- focused R&D and market access strategy, lessons about industry engagement in TB, and perspectives for pharma’s role in the broader global health landscape.

The case of bedaquiline presents an opportunity to understand J&J’s pursuit of a novel

TB drug and challenges faced in creating access to it. As a publicly traded, for-profit company,

J&J must balance its accountability to its shareholders with fidelity to its global health stakeholders. It could have been easy for J&J to sell bedaquiline or decide to donate it outright after receiving FDA regulatory approval and its accompanying incentives. This case demonstrates that there were many financial, regulatory, and reputational factors involved in the decision-making process, with long-term calculus seeming to suggest bedaquiline would bring sufficient benefits to warrant continued investment. However, the case also highlights the deep involvement of pharmaceutical companies in not just investing in R&D but making decisions that affect access of the drug. The complexity of the TB epidemic and the populations and places it primarily affects requires the global health community and J&J to learn from each other to solve a problem as complicated as the global TB epidemic.

Implications of bedaquiline for J&J

Leadership from the Wings

The narrative of bedaquiline today ties the discovery and development of the drug to the founder of Janssen Pharmaceutica, Paul Janssen, and a lifelong dream of his to find a cure for

TB. The reality of trying to get an unprofitable drug off the ground was in fact, as Andries has described it, “a rocky road” (Lougheed, 2017). While the discovery of bedaquiline involved a stroke of luck, but the development of the drug required bottom-up, politically-savvy maneuvering to continue to develop the drug until the evidence could speak for itself. Therefore, the story of bedaquiline is also a story about leadership, starting with Andries’ diagnosis of his situation: he was developing a potentially efficacious drug for TB within a profit-oriented

91 system, and understood the real and potential losses at stake. However, he persisted and stayed patient, biding his time to make a case to research management to expand clinical development only when he had sufficient evidence. Andries’s willingness to push boundaries and challenge beliefs within his capacity as a researcher characterizes a practice of leadership, which is neither based on power, authority, or influence (Heifetz, Grashow, & Linsky, 2009). His scientific breakthrough for bedaquiline was later rewarded with an Innovator’s Award from the European

Patent Office in 2014, but in the early 2000s, it surely was not comfortable to be nudging the company to support a drug with little commercial value.

There also appears to have been some appetite to push boundaries among the necessary authorizers of Andries’ work. It appears that J&J’s leadership was willing to engage in these challenges, with appropriate financial and non-financial incentives. The experience of Andries and the rest of the team at J&J working on bedaquiline required authorization from research managers; later, executives at J&J would also be involved when they decided to bring bedaquiline to market in-house and develop a new GPH organization to house and facilitate bedaquiline’s market entry, along with other products targeting markets with low profitability.

From a policy perspective, the challenges the scientists faced early on suggest the importance of ensuring that appropriate incentives are in place, particularly early-stage push incentives that could have helped the research team make the case for continued investment in R&D earlier on.

Without accelerated approval, the company would have had to face the unattractive prospect of financing expensive Phase 3 trials for bedaquiline without a guarantee of scientific “success” or regulatory approval, which would have likely put a damper on the company’s likelihood of actually bringing the drug to market. Further, the PRV served as a significant potential reward, such that by the time Phase 2 trials were complete, there was a large potential upside to seeking

92 regulatory approval at that point, without significant additional downside. However, the timing of these regulatory rewards came late in the process, such that smaller companies and less politically savvy groups of motivated scientists may not have been able to complete Phase 2 trials without more timely, incremental, incentives.

Further, this case study underscores the importance of understanding how a particular company is organized to better appreciate potential levers to change their behavior. For example, the way that GPH’s origins and organization reflects some of J&J’s reputational sensitivity highlights the value of “carrots” and positive reinforcement in guiding decision-makers’ interest in neglected diseases. Given the importance of executive authorization for costly resource outlays for projects with little commercial value, understanding these authorizers’ motivation is key. On the other hand, this case study also highlights the importance of understanding motivations when identifying when various, high-profile “sticks”, such as threats of compulsory licensing, are appropriate, as well as their likely demotivating impact on these decisionmakers’ motivations to continue company engagement in TB R&D – not just within J&J but across the industry.

Experimental Business Model Embodies Tensions of Investing in TB

J&J’s Global Public Health (GPH) team, formed under Janssen and primarily to manage bedaquiline, is in a difficult position where it isn’t quite regarded as philanthropy, as it is too resource-intensive and specialized for that. But, given the limited financial upside to selling TB drugs, GPH also doesn’t quite fit in pharma’s traditional commercial model. There’s a pressure for GPH to become self-sustainable – at least at no cost if no financial benefit to the firm – that can run counter to its goals of shoring up J&J’s reputation and meeting unmet needs. Although

GPH has considerable autonomy within J&J to innovate, being housed in a for-profit pharmaceutical giant means it will still be perceived as a cost center. There will continue to be considerable pressure to demonstrate some form of success; much of the financial upsides outlined in this paper, such as reputational benefits and partnerships, will be hard to measure and difficult to make the case for.

The story of J&J’s investment in bedaquiline suggests some of the hallmarks of adaptive challenges – persistent gaps between aspirations and reality, inadequate responses with the current portfolio, required learning and engagement of new stakeholders, a longer time frame, and disequilibrium and conflict results (Heifetz, Grashow, & Linsky, 2009). In fact, the structure of the GPH organization seems to embody these adaptive challenges, which will require learning and losses to address (Heifetz, Grashow, & Linsky, 2009), and which most pharmaceutical companies likely face today in an era of increasing pressure and outrage over high prices and traditional models of R&D. For example, the new business model through GPH has also led to a loss of autonomy because of disparate priorities of partnerships it is engaged with. J&J broadly, and GPH in particular, will need to consider the reputational risks of its partnerships, and weigh the benefits against this loss of autonomy and conflicting partner priorities.

Adaptive problems emerge from issues as fundamental as fulfilling both J&J’s profit motive and its Credo, to GPH’s more specific strategies – such as indecision between using tiered pricing or donating bedaquiline – to balance pressures to become self-sustaining while making life-saving products accessible. These questions are not going to be resolved easily, but are tied up in fundamental questions about the role of business in society.

Increased Exposure to Risks

For J&J, bedaquiline represented a major foray into meeting the pharmaceutical needs of primarily developing countries. However, it also exposes the company to many economic, social, and political risks related to operating internationally, such as the impact of interest and currency exchange rate fluctuations, changes in trade policies, or financial or social instability (J&J

Annual Report, 2017). One of the most important global trends in the health sector is pressure for pharmaceutical companies to lower their prices, stemming from governments’ moves to contain health care costs, restricted spending due to economic and budgetary constraints, or lack of social protection which reduces patient access.

At the same time that health care systems are looking to lower spending on health care, donor funding is also becoming less reliable as donor fatigue sets in and traditional donor countries are increasingly occupied with domestic issues. Traditional sources of financing, therefore, are not readily amenable to accommodating expensive new drugs unless their advantages are proven. Proving the value and cost-effectiveness of a drug like bedaquiline is therefore of paramount importance to J&J, which is inextricably tied to clinical performance.

Uncertainties around Clinical Outcomes

Receiving accelerated approval from the FDA, has been both a blessing and curse for

J&J’s bedaquiline program. Despite advantages of early approval, including lower and less costly clinical trial requirements up front and ability to claim laurels as the first new anti-TB drug to market in decades, the circumstances of bedaquiline’s approval have continued to haunt the drug. The morbidity imbalance observed during the Phase 2 trial, which earned bedaquiline its black box warning to patients about possible death, has been a major source of countries’ reservations for adopting the drug. Despite observational data that appears to establish the

95 relative safety of bedaquiline, particularly when compared to more toxic second-line drug alternatives, the WHO does not appear likely to accept these data as grounds for reconsidering its interim trials. The aggressiveness with which J&J engages in further R&D, though, will depend on its goals.

If J&J wants to expand use of its drug by convincing WHO to change its restrictive recommendations, it should prioritize completing its Phase 3 clinical trials to generate evidence that will support that change. The most dramatic examples of bedaquiline’s value and efficacy are being demonstrated in newer, shorter, bedaquiline-containing regimens for people with pre-

XDR-TB and XDR-TB. These patients have very few treatment options, but are getting a new shot at life, as demonstrated by the remarkable interim results of the Nix-TB trial, which J&J is conducting in partnership with the TB Alliance. The Nix-TB trial tests a three-drug, all-oral regimen, which includes bedaquiline, has been very effective thus far in treating treatment- intolerant or treatment non-responsive MDR-TB patients, pre-XDR-TB patients, and XDR-TB patients. Perhaps GPH should take a page from its scientists, who allowed the evidence of bedaquiline’s efficacy to speak for itself. For example, early adopters in South Africa and in other compassionate use programs have become bedaquiline’s biggest champions.

At the same time, J&J needs to prepare for potential challenges and uncertainties around clinical outcomes in Phase 3 and other combination trials, and in programmatic use. Most of the key clinical trials that are currently incorporating bedaquiline into various combination regimens will only be completed in 2021 (TB-PRACTECAL, endTB, STREAM stage II). Until then, as the company has already experienced, regulatory approvals in additional countries and greater demand for the drug will either be contingent upon clinical efficacy and safety that can be demonstrated from programmatic data, interim clinical trial data, and other small trials, or

96 continue to rely on WHO’s existing recommendation that bedaquiline be reserved as a last-resort treatment.

While additional clinical trials may establish evidence to support bedaquiline’s use in all patients with MDR-TB, the ideal target regimen profile would be a short, effective “pan-TB” regimen, which could be used to treat any type of TB. The global public health community is still grappling with how to prioritize pursuit of such a regimen, though bedaquiline’s inclusion in a pan-TB regimen would truly solidify the drug as a cornerstone of treatment, while expanding the market for bedaquiline use. However, supporters of the pan-TB push would likely prefer to have off-patent drugs involved; the 3P Project, a drug development initiative that explicitly aims to support the development of a pan-TB regimen, is run by MSF, which is a major advocate for drug access in low- and middle-income countries.

Underlying all of these concerns of clinical efficacy and safety are fundamental questions about how to structure the drug development process to demonstrate convincing evidence of efficacy and safety at appropriate scientific rigor, while minimizing clinical trial costs. Given the large number of possible combinations of drugs and dosages, some researchers are attempting to use less expensive methods than full-on clinical trials, such as predicting drug combinations and dosages based on experimental data, experiments in mice, and various mathematical techniques

(Low, 2017). As mentioned earlier, disagreement about acceptable biomarkers for success during

Phase 2 trials and inconsistency in Phase II methodology in tuberculosis has raised the possibility of adding Phase 2c trials, which would be longer than Phase 2a and Phase 2b trials. The goal of these changes would be to maximize success of Phase 3 trials. Indeed, J&J has seen success from focusing on generating evidence that can validate bedaquiline, allowing the evidence to speak for itself, as Andries did early on in its development.

Lessons from Bedaquiline on Public-Pharma Partnership in TB

The case of bedaquiline’s development and dissemination reveals important perspectives from the pharmaceutical sector for the public health community in fighting TB. First, pharmaceutical companies require appropriate incentives to engage in development of an unprofitable drug. Given their multiple accountabilities, most clearly and bindingly to their shareholders, pharmaceutical companies need to justify investments in disease areas that do not support their profit motive.

This does not mean that there is no intention to contribute to the world’s unmet needs. On the contrary, the dedication and creativity of scientists within J&J, like Koen Andries, to pursue an unlikely compound shows us that many individuals within large pharmaceutical companies are passionate about making a difference in the world. Their discoveries and contributions should be harnessed by the public health community, and within the context of large pharmaceutical companies, appropriate and timely incentives are critical to the survival of risky, early-stage projects.

Further, as mentioned earlier, even the most dedicated scientists rely on authorization from the organization, which despite its immediate profit motives, can also have indirect, longer- term, and non-financial motivations. As described earlier, many large pharmaceutical companies engage in drug development for neglected diseases for non-commercial reasons, such as corporate social responsibility, strategic positioning in emerging markets, and reputation

(Morans, 2005). The existence of organizations, mechanisms, incentives, and expertise minimize the risk of development and dissemination. For example, FDA’s accelerated approval of bedaquiline after only Phase II trials provided J&J with a major advantage for bedaquiline’s introduction, both by allowing J&J to be a first-mover in making the drug available and by

98 lowering clinical requirements, time, and expense to approval. Further, organizations like the TB

Alliance, the Global Drug Facility, and USAID’s technical assistance pathways all served as key facilitators, lowering costs and other barriers to entry while making continued development in

TB more attractive.

Since the 1998 creation of the Stop TB Initiative within the World Health Organization, the TB community has tested the waters for working with the private sector on TB control, in particular through the pharmaceutical sector. Aside from ability to leverage technical expertise and additional resources, there are a few underappreciated advantages for closer alignment with the pharmaceutical sector. Alliance with powerful multinational companies with strong relationships with donor countries can increase political will and financing for tuberculosis. For example, J&J’s position as one of the largest companies and employers in the United States gives it significant clout, and connections, in supporting global health funding in Capitol Hill. With bedaquiline and its other global public health portfolio, J&J has a larger stake in issues like maintaining, if not increasing, global health funding. Considering that the US government’s financial contributions to TB are all superlative – the most significant bilateral donor for TB, the largest funder of basic research in TB, and the largest funder of the Global Fund, which is in turn the biggest source of aid for TB – US government support for global TB control efforts is considerable. The emergence, indeed the predominance, of public-private product development partnerships like the TB Alliance serve as the most visible and formalized version of these partnerships, aiming to spur collaboration and shared expertise across the public and private sectors.

In addition to leveraging their strong relationships with donor countries, pharmaceutical companies remain central to any discussion about innovation in drug development.

Pharmaceuticals are able to maintain this position, given their ability to make large R&D investments and absorb the costs of potentially lengthy trials. Without greater public sector investment in TB R&D, the loss of funding from private pharmaceutical companies, though comparatively smaller, is still significant. Since the biomedical treatment model, including reliance upon extensive R&D to develop new tools, remains the foundation of the WHO’s End

TB Strategy, partnering with pharmaceutical companies will continue to be vital.

Lessons from Bedaquiline for Global Health

Failures of the Pharmacological-dependent Treatment Model

The development of new classes of antibiotics in the mid-20th century shifted the focus of

TB control to the delivery of drugs. Curative chemotherapy options created hope for people with

TB, and more recently, new and useful tools such as bedaquiline have the potential to shorten, simplify, and lower toxic effects of an arduous treatment regimen, and create options for people with MDR-TB, pre-XDR-TB, and XDR-TB where there once was none. Further, multi-drug approaches have successfully slowed the emergence of resistance (Fauci & Morens, 2012), and the treatment of infectious diseases is in itself a form of prevention (Fauci & Morens, 2012).

However, all antibiotics share an inherent weakness: targeted organisms almost always evolve mechanisms of resistance, and the human systems that use pharmacological tools are fallible.

The contested efficacy of DOTS and the need for new models for prevention, treatment, and control of TB has demonstrated that biomedical solutions alone are not sufficient, particularly for lowering population-level incidence.

The Sustainable Development Goals strengthen the case for addressing mutually reinforcing goals of eradicating tuberculosis, alleviating poverty, and achieving other social

100 objectives. Indeed, some have suggested putting TB at the core of the SDGs (Raviglione, 2017;

Fitchett et al., 2017) – an attractive prospect from the perspective of generating political will to invest in TB control and eradication among heads of state and non-health leaders. Directing serious attention toward achieving SDGs requires the TB community to look beyond tuberculosis toward universal health coverage and health systems strengthening. Given the historic organization of tuberculosis around centralized and vertical programming, and the existential threat the field faced when TB was sidelined in favor of primary care and health sector reforms in the 1970s and 80s, it remains to be seen how willing the community would be to subsume advocacy for its particular disease – and its particular approach.

Public Alternatives to Pharmaceutical Companies

Given the incentive misalignment that will always exist between pharma companies and meeting the needs of poor people in poor places, some have suggested that public or non-profit efforts could wholly replace the role of pharmaceutical companies in these issues (Yamey,

2002). If pharmaceutical companies are willing to share their expertise and their data, for example, non-profit drug developers could theoretically develop needed drugs on their own, which they could then provide to the world at cost. At the very least, systematic reviews of incentives for pharmaceutical investment in antibiotics suggest some merits of additional focus on “pull”, versus “push” mechanisms, in broadening the range of types of companies that could benefit, drawing additional value out of earlier investments, and guiding development to better ensure access to the drugs upon success (Renwick et al., 2016).

It is unclear whether completely relying upon the public sector and NGOs to lead drug development is preferable to having some active involvement from large pharmaceutical

101 companies. For example, TB Alliance has access to screen the compound libraries of many large pharmaceutical companies, such as Takeda (2016) and Novartis (2014), which are invaluable resources in service of non-profit-led pharmaceutical development. In addition, it is leading the development of drugs and regimens with compounds from AstraZeneca and Sequella, not to mention its royalty-free license from J&J to test new combinations with bedaquiline. Indeed, the

TB Alliance manages the largest pipeline of new TB drugs in history, and its collaborative model bolsters the prospects of succeeding on developing entirely new regimens, rather than a single drug at a time. The Medicines Patent Pool is another mechanism for innovation sharing that also promotes non-profit development and decision-making over that of pharmaceutical companies.

In an extreme version of this model, non-profit developers and generic companies could produce bedaquiline at low cost and sell the drug at low price, the TB Alliance could test regimens, and

J&J could wash its hands of a financially unattractive product.

Is it preferable for a company like J&J to effectively withdraw from R&D for neglected diseases like TB altogether, given perceived risks of intellectual property and price barriers to access? Is there an acceptable level of profit on private sector-developed products that could ameliorate both public health advocates looking to expand access and private sector companies looking to recoup R&D investments?

Though J&J had an option to “give the drug away” as theorized above, the company has resisted this impulse from the beginning, citing stewardship concerns as well as a desire to develop a self-sustaining model for R&D for such diseases. Other pharmaceutical companies that have withdrawn industry funding for R&D serve as counterpoints. Year-on-year TB funding from industry decreased by over a quarter (27%) from 2010 to 2013, almost entirely due to decreased investment in discovery and preclinical development efforts (Policy Cures). As

102 mentioned earlier, several companies have announced their complete withdrawal from TB drug development, following declining investments: in 2013, Pfizer licensed its Phase II sutezolid candidate to Sequella as part of the closure of its TB program; in 2014, Novartis announced the transfer of its TB drug compounds to the TB Alliance; and Astra Zeneca announced closure of its

Bangalore R&D site including its TB drug discovery program. All of these companies have been credited with partnering with the TB Alliance in the ways specified earlier, but in exchange, have ended their own early stage R&D efforts in TB. There is a chance, therefore, that “partnerships” in drug development could also absolve pharmaceutical companies from dedicating their own expertise and resources, if that is advantageous.

After working with the J&J GPH team for eight months, and as the case of bedaquiline shows, I have come to know many people in industry who truly believe, and are, making a difference in global health. To completely abandon that expertise seems a waste, though new mechanisms for incentivizing further production of antimicrobials, including anti-TB drugs, are clearly necessary. Pharmaceutical companies remain the primary agents that have successfully innovated and brought to market most of the new anti-TB drugs available today, and are not yet extricable for drug development, even as non-profits build expertise and facilitate collaboration.

Even the TB Alliance recognizes the importance of public sector involvement. In 2015, the TB

Alliance received $52 million in public support and other revenue to support its broad portfolio of drugs and regimens (TB Alliance Financial Statement, 2015). TB Alliance is most effective as a catalytic organization that attracts and coordinated resources from multiple partners. Its three main programs include R&D for new anti-TB drug candidates including outsourcing development to appropriate public and private partners, business development to negotiate terms that support development and access of anti-TB drugs while encouraging private sector

103 involvement, and public affairs and policy to advocate for public and private involvement in research. The private sector plays a clear role throughout these activities.

Engagement with entities such as the TB Alliance do come with some risks for J&J. On one hand, the TB Alliance develops complementary drugs and sponsors trials of future combination regimens to support the use of bedaquiline, lowering costs for J&J and improving understanding and adoption of bedaquiline as part of treatment therapies. However, the Alliance also has the power to shape the pipeline and therefore competition; for example, it may also develop more effective compounds than bedaquiline, prioritize drugs developed in-house in critical trials, or apply pressure to J&J to lower prices of bedaquiline at risk of exclusion. These are all theoretical musings about potential directions that drug development collaborations could take, but describe complicated dynamics in various partnerships. The global health community needs to find the balance between the PDPs like the TB Alliance serving as a complement by engaging pharmaceutical companies, and as a substitute, by challenging their relevance. Given the slim likelihood of success in drug development, society would benefit from the collective efforts of for-profit and non-profit developers.

Strengthening Health Systems

Regardless of the source of discovery and development, weak health systems will continue to thwart efforts to make new treatments available and accessible. The slow uptake of bedaquiline, even when courses are available for free through the Bedaquiline Donation

Program, underscores the fact that availability of new technologies does not necessarily lead to adoption. Weak health systems, cultural stigma of tuberculosis, and insufficient political will and leadership all contribute to poor uptake of new technologies like bedaquiline. This is not

104 surprising when taking into account the insufficient identification, detection, and treatment of people with MDR-TB even before these new technologies were available.

Introducing bedaquiline into the health systems of low- and middle-income countries has had knock-on effects on every other part of the health system, which may serve to either constrain or encourage its adoption. One way to understand the dynamics of bedaquiline adoption is systems thinking. Health systems have been described as open systems whose behavior is determined by the interactions of its components and contexts (Atun, 2012). These interactions can amplify certain components or outcomes in a positive feedback loop, or balance others with a negative feedback loop, with time lags and non-linear relationships that collectively create dynamic complexity (Senge, 1990). A holistic perspective on health systems over time, therefore, is important for understanding how innovations are adopted and diffused (Atun, 2012).

This lens is important when considering the impact that pharmaceutical innovations like bedaquiline may have on entire health systems. For example, political leadership on the order of

South Africa’s Minister of Health Aaron Motsoaledi is needed to galvanize a major shift in tuberculosis treatment. From a governance and stewardship standpoint, new regulatory and clinical regimes need to be developed to facilitate and monitor adoption and appropriate use, which is difficult in low- and middle-income countries that may have limited expertise or capacity.

Further, health workforces need to be trained to identify patients who could benefit from the new medicine and know how to administer it appropriately, and other medical supplies like complementary medicines in the combination regimen and appropriate diagnostics need to be procured in a timely manner and at affordable cost. All of these costs accrue merely to prepare for the uptake of new drugs and regimens; the direct cost of new treatments requires new

105 financing mechanisms to avoid catastrophic out-of-pocket expenses for affected patients and expand the fiscal space for TB treatment. In addition, the financial burden of adopting bedaquiline, not to mention the high cost of MDR-TB treatment in general, could be major deterrents to expanding case-finding and diagnosis of drug-resistant TB for decision-makers concerned about cost-containment and limited budgets. These are just several examples of how adopting a new health technology like bedaquiline requires systems changes, capacity, and leadership. The lack of all of these components, especially if health innovations are perceived as costs by individuals and health systems, deter access to new drug treatments and regimens for

TB.

The Role and Responsibility of Pharmaceutical Companies in Access to Medicines

Bedaquiline’s inclusion in the WHO’s Model List of Essential Medicines (EML) affirms the drug’s value to global health and given the vulnerability of its target population, puts J&J squarely in the midst of discussions about access to essential medicines. The EML, which has long been used by advocates to increase access, and in particular, affordability, provides broad guidelines for countries developing a list of medicines considered to be essential for well- functioning health systems. The concept of essential medicines is founded upon ideas that access to medicines are part of people’s right to health, which is enshrined in the WHO Constitution

(1946) and the Universal Declaration of Human Rights (1948). Further, the International

Covenant on Economic, Social, and Cultural Rights (1966) describes how people can realize the right to health through access to health facilities, goods, and services, emphasizing the centrality of access to medicines to discussion of the human right to health.

106

In 2016, the UN Secretary General’s High-Level Panel on Access to Medicines came to the conclusion that the “imbalance between human rights, intellectual property rights, and public health objectives is leaving people behind”, pointing out dual burdens of innovation and access.

First, the UNHLP observed that investment in research and development of health technologies is often impeded by low profit margins, resulting in many unmet health needs around the world.

Second, essential medicines remain out of reach for millions of people worldwide. The UNHLP came to several key recommendations, including: respecting and strengthening the legal landscape on intellectual property protection, affirming compulsory licensing and protecting access to health technologies; implementing additional models for R&D funding, such as strengthening public-private partnerships and product development partnerships, and providing grants and prizes; increasing transparency around production costs, access efforts, shared knowledge, and prices; increased investment in R&D, particularly in low- and middle-income countries; and creating a framework of accountability.

Clearly, there is some sense of obligation for the pharmaceutical sector in ensuring human health that must be negotiated in relation to governments’ responsibilities. While States have an obligation to make essential medicines available and accessible, UN Special Rapporteur

Paul Hunt has described a “shared responsibility” with pharmaceutical companies in his work applying the general framework from the 2000 Committee on Economic, Social and Cultural

Rights to specific health issues like access to medicines. States have criticized the pharmaceutical sector for setting prices too high, erratic drug donations, imbalanced research and development, lobbying for TRIPS-plus standards, inappropriate drug promotion, problematic clinical trials, and other practices that “obstruct a State’s ability to discharge its right to health responsibilities” (UN Special Rapporteur, 2006). Others have praised progress on “widespread

107 use of differential pricing, predictable and sustainable drug donations, and a renewed commitment to research and development into neglected diseases” (UN Special Rapporteur,

2006).

While there are few binding, independent accountability mechanisms for enforcing this shared responsibility, there is growing consensus among businesses that they, like all social actors, have some legal and ethical human rights responsibilities. The UN Global Compact, which J&J co-founded, includes over 2,300 participating companies, and affirms that businesses should support and respect protection of international human rights. In addition, some companies, J&J included, have voluntarily prepared their own guidelines and statements affirming their human rights responsibilities.

However, corporate responsibility is better judged by actions and outcomes, rather than words. In the absence of global accountability mechanisms, independent groups like the Access to Medicines Foundation have attempted to increase transparency and name corporations that are performing against expectations of responsibility for making medicines accessible and responsibly developing much-needed antibiotics. J&J’s positive performance in these independent benchmarks have largely been driven by its access efforts around bedaquiline. The positive cycle between recognition of J&J’s access efforts and J&J’s receptivity to positive reinforcement bodes well for GPH, the TB community, and broader relations between the pharmaceutical sector and global health.

However, as the UNHLP pointed out, systemic changes in the ways that pharmaceutical companies are rewarded and governments prioritize their citizens’ right to health are critical shape the world in which J&J operates and TB control efforts progress.

108

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