Mike Frick, TREATMENT ACTION GROUP

Lead Author: Mike Frick
Additional Authors: Erica Lessem, Brian Citro, Mihir Mankad, Colleen Daniels, Allan Maleche, and Kiran Raj Pandey
Organization: Treatment Action Group, University of Chicago, Save the Children UK, Stop TB Partnership, Kenyan Legal & Ethical Issues Network on HIV (KELIN)
Country: USA; UK; Switzerland; Kenya

Abstract

This contribution discusses how the current approach to innovation, detached from human rights standards and favoring the intellectual property (IP) interests of inventors and investors, has created an access to medicines crisis in tuberculosis (TB). Globally, development of and access to TB drugs and diagnostics remain severely constrained. As a consequence, TB has become the leading cause of death from an infectious disease, despite being preventable and curable since the 1950s. The paradigm under which TB research is financed, conducted, and owned has emerged as a major driver of inequitable access to TB medicines. Research and development for TB and other diseases now occurs along an IP maximalist orientation, principally defined by the Agreement on Trade-Related Aspects of Intellectual Property Rights. Reorienting innovation in ways that draw on States’ obligations to respect, protect, and fulfill the right to the highest attainable standard of health and the right to enjoy the benefits of scientific progress and its applications can help to resolve the policy incoherence that has placed the rights of inventors and investors in conflict with public health needs. We propose four rights-based strategies governments can pursue to reduce this incoherence: 1) more purposive public investments in research to benefit disadvantaged groups; 2) stronger public stewardship of research and its results; 3) greater public accountability over scientific agenda setting; and 4) clearer normative guidance to States on their obligations under the right to science. These solutions not only hold promise for TB, but also for other diseases for which current approaches to innovation have delayed, restricted or precluded access to medicines.

Submission

Globally, development of and access to new and repurposed drugs to treat tuberculosis (TB) remain severely constrained. Treatment for the nearly 10 million people who develop TB disease annually is lengthy—ranging from six months to over two years—and difficult to tolerate, making adherence challenging and fueling the rise of drug resistance. Eighty-percent of the estimated 500,000 people who develop multi-drug resistant tuberculosis (MDR-TB) each year receive no treatment at all.[i] Of those diagnosed and linked to care, most are treated with drugs developed decades ago that impart serious—and sometimes irreversible—adverse effects, including hearing loss and psychosis. More than two years after receiving marketing approval from stringent regulatory authorities, the first new TB drugs in 40 years—bedaquiline and delamanid—have reached fewer than 3,000 people, even though an estimated two-thirds of individuals with MDR-TB may benefit from receiving them.[ii],[iii]

As a consequence of these factors, TB—a disease that has been preventable and curable since the 1950s—kills 1.5 million people a year and is now the leading cause of death from an infectious disease.[iv] Limited access to TB testing and treatment is not only a result of market failures, inefficiencies, or inequitable global delivery systems. The paradigm under which TB research is financed, conducted, and owned contributes to inequitable access to TB medicines. Research and development (R&D) for TB and other diseases now occurs within a system built around a “maximalist approach to intellectual property protection,” principally defined by the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS).[v] By setting required minimum levels of protection without specifying upper limits, TRIPS and related trade laws have allowed an ever-upward expansion of intellectual property (IP) protection that has produced a growing misalignment between the interests of inventors and investors and public health.[vi],[vii] Using international human rights law to set ceilings on such protections would engender an approach to innovation that does not, from the outset, prioritize protection over access to medicines for TB and other diseases.

This submission details how the R&D system’s IP maximalist orientation has created an access to medicines crisis in TB. We begin by framing this crisis in terms of human rights—particularly the right to the highest attainable standard of health (e.g., Article 12 of the International Covenant on Economic, Social and Cultural Rights, or ICESCR) and the right to enjoy the benefits of scientific progress and its applications (e.g., Article 15 of the ICESCR)[viii],[ix]—before then illustrating how current approaches to innovation, detached from these human rights concerns, have undermined innovation and access to medicines for TB. We conclude by offering four human rights-based strategies governments can pursue to realign the interests of inventors and investors with public health: 1) more purposive public investments in research to benefit disadvantaged groups; 2) stronger public stewardship of research and its results; 3) greater public accountability over scientific agenda setting; and 4) clearer normative guidance to states on their obligations under the right to enjoy the benefits of scientific progress and its applications.

Human rights compel States to act on R&D as a determinant of access to medicines

Framing the access to medicines crisis in relation to the rights to health and scientific progress can help to resolve the current incoherence between the interests of inventors and investors and public health. While there has been much attention paid to States’ need to intervene “downstream,” where approved health technologies are connected to people in need, there has been much less discussion of what States’ obligations are in the “upstream” R&D space, so that new tools are developed in ways that meet global health needs.[x] Both rights establish legal obligations that States can meet through measures that address shortcomings in the current R&D system. These approaches must limit, and where possible eliminate, all scientific, regulatory and commercial barriers to access to health technologies.

Recognizing the interrelation of the rights to health and scientific progress may help governments see and act on the consequences IP policies hold for access to medicines. The right to health requires States to take necessary steps toward “prevention, treatment, and control” of diseases.[xi] General Comment 14 of the Committee on Economic, Social and Cultural Rights (CESCR) clarifies that the right to health encompasses inter alia a requirement that health goods and services are available.[xii] For diseases like TB, where inadequate and outdated tools hinder a vigorous public health response, fulfilling the right to health requires States to ensure health technologies are available, on a nondiscriminatory basis, through promotion of medical research, especially for vulnerable or marginalized groups. General Comment 14 references medical research in several places, noting that fulfilling the right includes “the promotion of medical research and health education.”[xiii]

Where current approaches to R&D delay, restrict or preclude access to medicines, States may have additional justification to intervene. ICESCR Article 15 establishes the right of everyone to enjoy the benefits of scientific progress and its applications, without discrimination. Scholars and scientific professional associations have proposed that this requires States to engage in both the development and diffusion of science, including “investing in R&D and creating incentives for innovation to address forms of suffering experienced by [vulnerable groups].”[xiv] A plain language reading of the treaty text indicates that access is a cornerstone of the right, and that this entails enjoying the actual—and in the case of health technologies, tangible—applications of scientific progress (i.e., access to the benefits of scientific progress go beyond mere sharing in the diffuse benefits that accrue from general scientific advancement).[xv] Consequently, fulfillment of this right requires State action to ensure that the means of scientific progress, where they involve protectionist measures as under the current patent regime, do not come at the expense of access to medicines or other applications of discovery and knowledge.

Current approaches to innovation restrict access to medicines for TB

Attention to TB raises a number of important considerations for the High-Level Panel’s work. First, TB demonstrates how the consequences of the misalignment of the interests of inventors, investors, human rights and public health will be increasingly borne by countries that are graduating from aid eligibility.[xvi] TB primarily affects poor people, most of whom live in middle- and upper middle-income countries.[xvii] Together, Brazil, Russia, India, China and South Africa (the BRICS countries) account for 46% of incident TB cases, 40% of TB deaths and 56% of new cases of MDR-TB.[xviii] Second, resolving how current approaches to innovation stymie access to medicines for TB may illuminate strategies for tackling the threat of antimicrobial resistance (AMR) more broadly defined. The global rise of MDR-TB, and the paucity of new drugs and diagnostics to combat it, illustrates how existing market-driven approaches to innovation have fallen behind the development of drug-resistance.

Over time, the failure of the R&D system to replace or improve inadequate TB treatment regimens has contributed to the changing nature of TB disease itself, whereby strains of a once curable disease have turned chronic and deadly. The majority of TB drugs were developed decades ago, and several have never been studied for TB under the rigorous conditions of randomized, controlled trials. Only two new drugs from new drug classes have been approved to treat TB in the last 40 years: bedaquiline (developed by Janssen and approved by the United States Food and Drug administration in 2012) and delamanid (developed by Otsuka and approved by the European Medicines Agency in 2014).[xix] Lack of access to timely TB diagnosis and drug susceptibility testing has further contributed to poor treatment outcomes; globally, cure rates for MDR-TB are around 48%.[xx] Scale-up of new TB diagnostics like GeneXpert MTB/Rif, a test that can diagnose TB and resistance to the first-line drug rifampicin in less than two hours, remains modest. Most national TB programs continue to rely on sputum smear microscopy, which misses up to half of all TB cases (and even more among children and people with HIV).[xxi]

The inadequacy of current TB prevention, diagnosis, and treatment options can be traced back to the ways in which limited funding for TB R&D has delayed the development of new health technologies and forced compromises in specific research programs. Treatment Action Group has tracked global funding for TB R&D each year since 2006 and found that annual combined spending on TB research by public, private, philanthropic, and multilateral institutions has never exceeded $700 million per year, barely one-third of the projected $2 billion needed.[xxii] After increasing from $358.5 million in 2005 to $636.7 million in 2009, funding for TB R&D has remained stagnant since the global financial crisis. Flat funding in nominal terms masks a real trend of falling funding, since inflation decreases the purchasing power of flat budgets, and the costs of biomedical research have risen faster than inflation.[xxiii] This underfunding is especially acute for R&D for TB drugs, which in 2014 received $243.3 million in funding, one-third of the $740 million experts estimate the world must spend on TB drug development each year to eliminate TB.[xxiv]

In addition to the low absolute level of funding, the structure of TB R&D financing jeopardizes progress by concentrating resources among a small pool of donors. This has left the field vulnerable to shifting donor priorities and even the withdrawal of funders, especially from the private sector.[xxv] Sixty percent of TB research funding comes from public agencies, and 62% of public funding comes from a single country: the United States.[xxvi] Funding from non-public sectors is also highly concentrated; 86% of philanthropic support for TB R&D in 2014 came from the Gates Foundation, and 54% of pharmaceutical industry funding came from a single company: Otsuka.[xxvii]

Structural shifts in the pharmaceutical industry in the post-recession period have intensified this reliance on public funding. In 2014, the pharmaceutical sector spent just $98.6 million on TB research, a decline of one-third from 2011.[xxviii] Three major pharmaceutical companies (Pfizer, AstraZeneca, and Novartis) have closed their TB research programs since 2012 under an industry-wide pivot away from anti-microbial research.[xxix],[xxx],[xxxi] Newly developed antibiotics are not expected to generate blockbuster sales, leading major pharmaceutical companies to focus on developing treatments for chronic illnesses.[xxxii] As pharmaceutical companies pull back from TB and anti-microbial research, the onus of responsibility to respond to drug resistance will increasingly fall on country governments.

Even as pharmaceutical companies have reduced their funding for TB research, they have retained ownership over the trial data, patents, and marketing rights associated with most of the compounds in the TB drug pipeline. This asymmetry between the source of financing and ownership of the products has undermined access to medicines in several ways. First, the public has been asked to pay twice for new technologies—first through taxpayer-funded R&D, and then to purchase new drugs and diagnostics at prices set by the companies that benefitted from public research dollars.[xxxiii] This dynamic delayed the introduction of TB drug rifapentine, owned by Sanofi, in the United States following a groundbreaking phase III clinical trial funded and conducted by the U.S. Centers for Disease Control and Prevention that showed rifapentine paired with isoniazid could reduce treatment of TB infection from 9 months of daily therapy to just 12 once-weekly doses.[xxxiv],[xxxv] Although the U.S. government funded this research, public TB programs in the U.S. could not afford to buy rifapentine at the original price set by Sanofi.[xxxvi] U.S. TB programs were only able to access rifapentine after an advocacy campaign by civil society organizations, patient groups, and academic institutions led Sanofi to reduce the price by 57%.[xxxvii] Global access to rifapentine is even more restricted. Despite being studied through a series of public-private research collaborations in 12 countries, rifapentine is only registered and available in the United States.[xxxviii]

Second, IP protections have undermined the development of new TB drug regimens. The need for multiple drug candidates is essential, since treating TB requires combination therapy to protect against the development of resistance. Yet there are few new drugs to study, and even those recently developed have not yet been studied in combination due to the reluctance of manufacturers to collaborate and share IP, and to the slow progression of research resulting from insufficient resources.[xxxix] New TB drugs bedaquiline and delamanid were studied as add-ons to existing regimens, potentially improving their efficacy, but doing nothing to address the toxicities, intolerabilities, drug interactions, and long duration of existing regimens. Bedaquiline and delamanid each received approval and marketing authorization with little to no data about the safety and efficacy of their use in combination with each other, with repurposed drugs, or with other new drugs under development. This lack of data contributed to the relatively narrow indications for bedaquiline and delamanid’s use under initial WHO guidance and has slowed their global uptake.[xl]

Third, inadequate financing combined with a maximalist approach to IP protection means that many promising TB drug compounds get stuck in early stages of development while remaining unavailable for study by outside investigators, including those associated with public research networks, universities, or non-profit product development partnerships. For example, TB drug candidate sutezolid entered phase I trials in 2009. It then took four years to complete just three phase I and phase IIa trials—each under two weeks in duration. Even though the drug showed promising signs of safety and efficacy, sutezolid has yet to begin phase IIb trials more than two years after the phase IIa trial ended.[xli]

Proposed policy solutions to advance human rights and promote public health

The following recommendations offer ways to recalibrate existing approaches to innovation that favor the rights of inventors over public health. Acting on these ideas would not mean invalidating the rights of inventors. Rather, these proposals acknowledge that knowledge is a resource that grows rather than diminishes when shared.[xlii] Where knowledge advancement results in the development of new health technologies, such sharing may be required to uphold human rights and advance public health

(1) Public investment. Fulfilling the right to scientific progress requires governments to purposively allocate resources toward research that addresses harms disproportionately felt by poor and marginalized communities.[xliii],[xliv] Targeted government investments may be essential to meet innovation needs for diseases like TB for which market-driven R&D schemes result in chronic underfunding and little scientific advancement.

(2) Public stewardship. Purposive public investments in science must be accompanied by mechanisms that create the conditions required for equitable access to medicines. Here, states can draw on several tools to ensure taxpayers do not pay twice for innovation or fund research that remains privately held and inaccessible.

a.     Patent pooling and non-exclusive licensure of IP. Governments could require that inventors, as a condition of receiving public funding, agree to pool IP with other developers. When paired with upfront grants (i.e., push funding) and prizes for meeting pre-determined development milestones (i.e., pull funding), patent pooling can form a central pillar in a comprehensive strategy for accelerating research by removing barriers to collaboration. For example, Médecins Sans Frontières has proposed the combination of push, pull and pool mechanisms under the so-called 3P Project as a way to incentivize the development of new TB drug regimens.[xlv]

b.     Technology and knowledge transfer. The global scale-up of antiretroviral therapy for treating HIV has demonstrated that generic competition is one of the most powerful tools for expanding access to medicines.[xlvi] Patent pools alone will not enable generic competition; for this to occur, states will need to create platforms for the transfer of technology, manufacturing process information, and industrial know-how from originator to generic companies.[xlvii] Pharmaceutical companies themselves frequently transfer technology to individual generic manufacturers to expand their production reach in specific regions.[xlviii] Instead of relying on these bilateral technology transfer arrangements—which reflect the protectionist concerns of TRIPS rather than public health needs—states should establish more transparent initiatives for sharing technology among a wide array of partners. For example, the WHO has successfully used technology transfer hubs to increase global production capacity of influenza vaccine.[xlix] Agreements on technology transfer should be brokered in early stages of R&D and could come as a condition for receiving government funding.

c.      Legal instruments. Other ways to align public funding and public ownership include creating legal instruments to review the impact of IP protection on access to medicines. This could include public funders reserving march-in rights allowing them to reclaim innovations from companies that fail to make them publicly available (as allowed in the United States under the 1980 Bayh-Dole Act).[l] Other legal mechanisms might include reviewing patent applications with respect to whether granting a patent would likely result in an outcome that violates human rights. Countries could also create avenues for third parties to oppose patents on health technologies based on human rights grounds either before or after patents have been granted (as is currently possible in India).  

(3) Public accountability. Ensuring that the above mechanisms effectively broaden access to medicines will require building accountability through public participation in decision-making about science and technology. The input of diverse stakeholders into major decisions about scientific prioritization and governance upholds the human rights principle of participation and could help to ensure that research addresses the needs of vulnerable communities. Participation—and the accountability it engenders—should unfold on multiple levels. Nationally, governments should involve public stakeholders in setting national plans of action to address unmet research needs. These plans should come with clear timetables, goals, and milestones, enabling public groups to track States’ progress.[li] Second, communities affected by a particular disease should be empowered to participate in research as more than just trial participants. One effective strategy in HIV and TB research has been the involvement of community advisory boards in setting the research agenda, overseeing the conduct of trials and advocating for research results to be made accessible through the translation of evidence into policy and practice.[lii]

(4) Normative guidance to States on the right to scientific progress. The UN CESCR should consider drafting a General Comment articulating the content and scope of Article 15(b) in the context of innovation of and access to health technologies. To date, normative guidance on Article 15 has focused on Article 15(c) regarding IP protection (General Comment 17),[liii] and Article 15(a) regarding the right to take part in cultural life (General Comment 21).[liv] This has left a gap in State understanding of obligations under Article 15(b), the component of Article 15 that recognizes “the right of everyone to enjoy the benefits of scientific progress and its applications.” The formation of a General Comment would build on the 2012 Report of the Special Rapporteur in the Field of Cultural Rights, which recommended “further work be done to enhance the conceptual clarity of the right.” In addition, the development of human rights indicators for measuring state progress in respecting, protecting, and fulfilling this right would help States translate core obligations under the right into operational standards.[lv]

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[11] ICESCR (see note 8), para 12(2)(c).

[12] UN Committee on Economic, Social and Cultural Rights. General Comment No. 14, The right to the highest attainable standard of health. 2000. UN Doc. No. E/C.12/2000/4, para 12(a)

[13] Ibid, para 36.

[14] American Association for the Advancement of Science Board of Directors. AAAS statement on the human right to the benefit of scientific progress. 16 April 2010. Available from: http://www.aaas.org/sites/default/files/migrate/uploads/Article15_AAASBoardStatement.pdf.

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[24] Frick M (see note 22).

[25] Ibid.

[26] Ibid.

[27] Ibid.

[28] Ibid.

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[43] American Association for the Advancement of Science Board of Directors (see note 14).

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[54] UN Committee on Economic, Social and Cultural Rights. General Comment No. 21, The right of everyone to take part in cultural life; 2009. UN Doc. No. E/C.12/GC/21.

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