Lead Authors: Grania Brigden and Katy Athersuch
Organization: Médecins Sans Frontières- Access Campaign
*We present this submission on behalf of Médecins Sans Frontières- Access Campaign, the WHO Global TB Programme, Global TB Coalition of Advocates (GCTA) and Global TB Community Advisory Board (TB-CAB), the Stop TB Partnership (STBP), the TB Alliance and the International Union Against Tuberculosis and Lung Disease (The Union).
We present to you the 3P Project which aims to rapidly deliver affordable, effective new regimens for the treatment of TB through an open collaborative approach to conducting drug development and through novel approaches to financing and coordinating R&D. This project provides a model for public health needs-driven R&D, which on a disease-specific scale demonstrates how the policy incoherence between the justifiable rights of inventors, international human rights law, trade rules and public health can be remedied in the context of health technologies.
TB is a disease which occurs mainly in the developing world and the lack of R&D into treatments for the disease reflects the lack of financial incentives for developers. The 3P Project overcomes this by providing funding for R&D activities upfront (push); funding to incentivise R&D through the promise of financial rewards on the achievement of certain objectives (pull); and linking these financial incentives to commitments to IP and data pooling in order to foster open collaborative research, accelerate the development of combination regimens and enable affordable access through the fair licensing of the final products for competitive production (pool). As such, the Project “de-links” the incentive to innovate from high product prices, guaranteeing affordability and availability of the newly developed regimens.
The structuring of incentives rewards the efforts of inventors, while ensuring that the data and IP generated are pooled and made broadly available, thus promoting the human right to enjoy the benefits of scientific progress (1) and the right to health (2). In accelerating the delivery of urgently needed treatment regimens to treat all forms of TB, it will help to end the epidemic, thus helping to achieve an important target agreed in the Sustainable Development Goals (SDGs).
Last year, the global community agreed to ambitious targets in the Sustainable Development Goals (SDGs) to promote healthy lives. In particular, SDG 3 aims to end the tuberculosis (TB) epidemic by 2030. It also promises to support the research and development (R&D) of medicines for diseases that primarily affect developing countries, and to provide access to affordable medicines (3). For TB, these two targets are inextricably linked, as the current medicines at our disposal are not up to the challenge of ending the TB epidemic. There is a need to support greater investments in R&D in TB drug development, and to ensure that the R&D is conducted in a manner that ensures broad and equitable access.
TB mainly affects people living in low- and middle- income countries with 95% of cases occurring there (4). 9 million people became infected with drug-sensitive TB and 1.5 million people died from the disease in 2014 alone (5). With the advent of new diagnostics like GeneXpert, the confirmed numbers of multidrug-resistant (MDR) TB cases are rising and programmes are unable to cope. Of the 480,000 cases of MDR-TB estimated to have occurred in 2014, only about a quarter of these – 123,000 – were detected and reported. In 2014, an estimated 190,000 people died of MDR-TB (6).
MDR-TB treatment is particularly difficult, because it is long—two years of treatment including eight months of daily injections and a total of more than 14,600 pills to swallow—and because many of the medicines used have toxic side effects such as deafness, psychosis and severe nausea. Globally, an estimated 3.3% of new TB cases and 20% of previously treated cases are MDR-TB. Only 50% of treated MDR-TB patients were successfully treated, and costs can be very high. An estimated 9.7% of people with MDR-TB have extremely drug-resistant TB (XDR-TB), for XDR-TB (reported by 105 countries by 2015) (7) cases treatment is even longer, more expensive and the success rate is even lower at only 13%.
The ultimate goal in TB treatment is the development of new treatment combinations to effectively, safely, quickly, affordably and simply treat all forms of TB. In the immediate term there is an urgent need to improve the treatment for MDR-TB. In order for these new treatment combinations to be developed the status quo must be transformed to deliver:
a healthy TB drug pipeline with a number of compounds in all phases of development. The pipeline for new TB drugs is weak; there are only 8 new chemical entities in clinical development (8).
an increase in investment; the current spending of $674 million on all TB R&D (vaccines, diagnostics and treatment) (9) is only 33.7% of the $2 billion annual funding target outlined in the 2011–2015 WHO Global Plan (10). Of particular concern is the continued decrease in private sector investments which stood at just 15% of overall funding in 2014 (11).
an open collaborative R&D approach that reduces risks and costs associated with testing multiple drugs for combination treatments by incentivizing research organizations to share scientific data, clinical trial results as early as possible and to conduct medically appropriate research on combinations of compounds.
a de-linking of R&D cost from prices to ensure affordability and access of resulting medical tools
The ‘3P Project’ aims to rapidly deliver affordable, effective new regimens for TB through an open collaborative approach to conducting drug development and through novel approaches to financing and coordinating R&D. The 3P Project implements three mechanisms to facilitate the necessary and appropriate R&D for TB regimens:
· pull funding to incentivise R&D activities through the promise of financial rewards on the achievement of certain R&D objectives (i.e. through milestone prizes)
· pooling of intellectual property (IP) and data to ensure open collaborative research and affordability through the fair licensing for competitive production of the final products
· push funding to finance R&D activities upfront (i.e. through grants)
II. BACKGROUND: WHY IS TB DRUG R&D FAILING TB PATIENTS?
FOCUS ON DEVELOPMENT OF SINGLE DRUGS, NOT NEW REGIMENS. In 2012, the first new TB drug in 50 years received accelerated approval for use in treating MDR-TB, and a second new drug was approved in late 2013 (12). TB must be treated with a combination of drugs, but a lack of collaboration and transparency means that clinical trials to test these two new drugs in combination in order to ensure they can be safely combined and then to build a new, better regimen will not be completed for several years. Many organisations working in the area of regimen development, including TB Alliance, the UK’s Medical Research Council (MRC), the Open Source Drug Discovery project (OSDD) and RESIST TB, have encountered obstacles in accessing new drug compounds for testing as part of improved treatment regimens. There is currently no IP licensing mechanism linked to financial incentives – either grants or prizes - to incentivize the collaborative, open research needed to stimulate regimen-based R&D activities.
INADEQUATE FINANCIAL INCENTIVES FOR COMPANIES. The market for TB regimens is far less lucrative than for other diseases and is marked by chronic underinvestment; this translates into slow or stalled scientific progress, as promising drug candidates languish for lack of a business case. Private-sector investment in TB R&D has fallen by a third since 2011 (13), and since 2012 Pfizer, AstraZeneca, Novartis and Vertex have all withdrawn from TB drug development, closing R&D facilities. The lack of market incentives makes it difficult for research organizations to enter the TB R&D field and to take TB drug candidates through to late-stage clinical research, leaving significant gaps in the pipeline: there are only 8 new TB drug candidates in clinical development and there are no ongoing late stage clinical trials recruiting patients to test all new drug regimens, with the exception of one- the Nix TB trial in XDR-TB. (14) Many of the compounds currently in Phase II and Phase III are older “repurposed’ compounds that don’t represent investments by commercial developers. With the exception of bedaquiline and pretomanid, new drugs are currently being developed as single products and are not involved in combination trials or new regimen trials until after receiving regulatory approval.
LACK OF FINANCIAL SUPPORT TO PROGRESS PRECLINICAL COMPOUNDS. In early-stage and preclinical research, the majority of TB compounds are being developed by public institutions, small companies or product development partnerships (PDPs), and it is unclear if they have the necessary capital and resources to bring an adequate number of new products forward to Phase I trials. For example preclinical development of the new drug candidate PBTZ169 was funded by the European Commission, but further progression of this potential new chemical entity has stalled as there are no dedicated funding streams available for the next stage of development (15).
ACCESS AND AFFORDABILITY NOT GUARANTEED: When new TB products come to market, they may not be affordable or accessible in countries where the disease burden is highest. For example, the new TB drug bedaquiline will cost US$900 in low-income countries and US$3,000 in middle-income countries for a 6-month regimen and Delamanid will be priced at US$1,700 in low-income countries, to which the cost of several other drugs will need to be added (16).
III. A JOINT POOLING & FUNDING MECHANISM TO PROMOTE INNOVATION AND ACCESS
The ‘3P Project’ creates a new open collaborative framework for regimen development based on the sharing of data, the pooling of intellectual property and the creation of incentives for multiple actors to enter the R&D process in order to accelerate drug regimen development timelines.
Opening up the pipeline to promote collaboration for drug combinations and regimen development and offering incentives to facilitate progression will help ensure that preclinical compounds are brought forward to clinical trials. Drug-drug interaction and potential beneficial drug combinations can be discovered sooner if products are tested together at an early stage, which will accelerate the development of new regimens. The increased investment and structuring of funding through both push and pull mechanisms will dramatically increase the number of compounds in the clinical development pipeline, enhancing the work of PDPs such as the TB Alliance in designing and testing regimens for all forms of TB.
In order to ensure affordability of the final medicines, the 3P Project separates (or “de-links”) the cost of R&D from the price of the resulting treatments. Once a regimen receives regulatory approval, the individual drugs or fixed-dose combinations could be licensed to multiple manufacturers with proven capacity to produce quality-assured drugs through the patent pool, allowing competition to lower prices to a sustainable level in developing countries. Regimen prices would be determined independent of the cost of R&D. In this way, international donors, developing country governments and patients will not be asked to cover the cost of medical R&D through the price they pay for the treatment.
The 3P Project proposal offers benefits over the current TB R&D framework by:
Reducing duplication of research efforts, thereby saving time and money
Reducing the risks associated with developing potential combinations early in the R&D process
Accelerating the development of all-new drug regimens
Reducing the risk of resistance to new compounds by ensuring their use as part of regimens
Coordinating disparate sources of funding and linking financial rewards to an obligation to share scientific and clinical data and IPR
Separating (“de-linking”) R&D costs from the final price of TB combination regimens
For a schematic representation of the proposed mechanism including prizes, grants and patent pooling, please follow this link: http://www.msfaccess.org/sites/default/files/MSF_assets/TB/Photos/TB_3P-diagram_0.jpg
IV. IMPACT ON POLICY COHERENCE
By improving the way TB drug development is conducted, the 3P Project aims to bring greater coherence in the rules governing the rights of inventors, international human rights, trade rules and public health objectives. While the current intellectual property rules embedded in global trade laws may provide an effective incentive mechanism for R&D into diseases affecting high-income countries, it is well-recognised that this is not the case for diseases affecting predominantly poorer countries such as TB (17). The Project aims to overcome this market failure through an innovative funding model that de-links the cost of R&D from the price of the final product (18). In doing so, it rewards the efforts of inventors (through both “push” and “pull” financing), while ensuring that the data and IP generated in the development efforts are pooled and made broadly available, thus promoting the human right to enjoy the benefits of scientific progress (19) and the right to health (20). And by ensuring that the incentive mechanisms are targeted towards specific development efforts, the Project aims to speed the development of effective TB regimens that will help to end the epidemic, thus helping to achieve an important target that was globally agreed in the SDGs. Importantly, although the Project addresses just one pressing public health need in TB, its successful implementation will have far-reaching effects towards achieving greater policy coherence globally.
V. IMPACT ON PUBLIC HEALTH
According to the WHO, TB is now the leading cause of death from infectious disease globally (21). Ending the TB epidemic has been recognised as a priority public health target in the SDGs, but achieving that target will be difficult, if not impossible, with the existing arsenal of TB medicines. The 3P Project aims to address this pressing need by adopting a public health-oriented model for TB drug development. Rather than relying on commercially-driven decisions regarding allocation of R&D efforts, the Project will align the incentives for R&D with public health needs. The data and IP that is generated through the Project will be managed with public health considerations in mind, and with the cost of R&D “de-linked” from the price of the final products, affordability and availability of the new regimens developed through the Project will be guaranteed.
VI. ADVANCING HUMAN RIGHTS
The right to health is enshrined in a number of international instruments, including the Universal Declaration of Human Rights and International Covenant on Economic Social and Cultural Rights (ICESCR) (22). The WHO Constitution declares that “the enjoyment of the highest attainable standard of health is one of the fundamental rights of every human being (23).” General Comment 14 of the UN Committee on Economic, Social and Cultural Rights identifies access to essential medicines is a core part of the right to health, and applies the principles of availability, accessibility, acceptability and quality to this right (24). The 3P Project will advance the right to health for people living with TB by making available safer, less toxic, simpler, more effective TB regimens of shorter duration. The Project, by de-linking the cost of development from the price of the medicine, will ensure that the new treatments are made accessible and affordable. By driving R&D efforts with public health considerations in mind, the Project will ensure that the medicines that are developed will be acceptable to TB patients and their specific needs. And by including stringent quality standards in the terms of the non-exclusive IP licences that will be made available to qualified licensees, the Project will ensure that all medicines will be of good quality.
The Universal Declaration of Human Rights and the ICESCR also enshrine the human right to enjoy the benefits of scientific progress and its applications (25). Although not a human rights instrument, the Agreement on Trade-Related Aspects of Intellectual Property adopts a similar norm in declaring that the protection of IP should contribute to the “dissemination of technology and in a manner conducive to social and economic welfare (26).” The Special Rapporteur in the field of cultural rights has expounded on the right to enjoy the benefits of scientific progress in the context of access to medicines, and has recommended that “states and other stakeholders further develop incentive mechanisms that delink research and development from the price of products (27),” and observed that “collective management of patent rights is an approach that might be extended to promote access to medicines (28).”
The Project already relies on the participation and support of many of the leading technical and political organisations in the field of TB, including TB Alliance (TBA), Médecins Sans Frontières (MSF), the Stop TB Partnership (STBP), The South African Medical Research Council (SAMRC), The Union, the Critical Path Institute (C-PATH), an individual nominated by civil society groups (CS) and, with its recent entry into tuberculosis, the Medicines Patent Pool. Several governments have also expressed their support for the initiative, and the World Health Organization has contributed to its further development. In 2014, an early draft of the project was selected by the WHO European Region as a possible Health R&D demonstration project (29). Since then, the project has evolved further with significant additional buy-in from TB stakeholders and strong interest from several high-burden TB countries. Strong political and financial support will be important in order to operationalize the push and pull funding elements of the initiative.
The institutional structure is envisaged as a collaboration between a number of existing organisations in TB, rather than the establishment of a new organisation, and would rely on expertise of existing technical bodies. An interim Steering Committee is in place to guide and support the implementation of this proposal. Implementing partners and steering committee members include the International Union Against Tuberculosis and Lung Disease (Union), MSF, Stop TB Partnership (STBP), a member of civil society, the TB Alliance, the South African Medical Research Council, the Medicines Patent Pool (MPP) and the Critical Path Institute (C-Path). Within the virtual secretariat, the Union will be the main project coordinator. Additionally there will be four other main lines of work; the scientific advisory committee, IP licensing for innovation and access (led by MPP), advocacy communication and resource mobilization (led by STBP) and data pooling (led by C-Path).
Bibliography and References
(1) Universal Declaration of Human Rights (Article 27) http://www.ohchr.org/EN/UDHR/Documents/UDHR_Translations/eng.pdf; International Covenant on Economic, Social and Cultural Rights (Article 15, 1b) http://www.ohchr.org/Documents/ProfessionalInterest/cescr.pdf; see also Special Rapporteur reports: A/HRC/20/26; A/70/279
(2) ICESCR (Article 12); UN Committee on Economic, Social and Cultural Rights (General Comment 14)
(3) United Nations (2015), Transforming our world: the 2030 Agenda for Sustainable Development. A/RES/70/1
(4) WHO (2015), Tuberculosis. Fact sheet N°104, http://www.who.int/mediacentre/factsheets/fs104/en/
(5) WHO (2015), Global Tuberculosis Report 2015 (page 5) http://www.who.int/tb/publications/global_report/gtbr2015_executive_summary.pdf
(6) WHO (2015), Global Tuberculosis Report 2015 (page 2)
(7) WHO (2015), Global Tuberculosis Report 2015 (page 2)
(8) Working Group on New TB Drugs (2016), http://www.newtbdrugs.org/pipeline.php (The 8 compounds are: TBA-354 (Nitroimidazole); Q203 (Imidazopyridine); Sutezolid; SQ109; Pretomanid; Bedaquiline; Delamanid; AZD5847) and Treatment Action Group (TAG) Pipeline Report (2014) http://www.treatmentactiongroup.org/sites/g/files/g450272/f/201407/2014%20Pipeline%20Report%20Full.pdf
(9) Treatment Action Group (TAG), (2015), 2015 Report on Tuberculosis Research Funding Trends, 2015- 2014: A Decade of Data, http://www.treatmentactiongroup.org/sites/g/files/g450272/f/201511/TB_FUNDING_2015_WEB.pdf (page 1)
(10) WHO and Stop TB Partnership (STBP), The Global Plan to Stop TB 2011 – 2015: Transforming the Fight Towards Elimination of Tuberculosis, http://www.stoptb.org/assets/documents/global/plan/tb_globalplantostoptb2011-2015.pdf
(11) Treatment Action Group (TAG), (2015), 2015 Report on Tuberculosis Research Funding Trends, 2015- 2014: A Decade of Data, (Page 12)
(12) Treatment Action Group (TAG), (2015), 2015 Report on Tuberculosis Research Funding Trends, 2015- 2014: A Decade of Data, (Page 5).
(13) WHO (2015), Global Tuberculosis Report 2015, and TAG (2015), 2015 Report on Tuberculosis Research Funding Trends, 2005-2014: A Decade of Data
(14) TB Alliance, http://www.tballiance.org/downloads/NixTB/NixTB_factsheet.pdf
(15) News Medical, (2014), ‘EPFL sets up foundation to release antibiotic for tuberculosis’, http://www.news-medical.net/news/20140312/EPFL-sets-up-foundation-to-release-antibiotic-for-tuberculosis.aspx
(16) MSF, (2015), Out of Time: Access to Treatment for DR-TB, http://msfaccess.org/sites/default/files/TB_Out_of_Time_DRTB_Drug_Briefer-ENG_Dec-2015.pdf
(17) WHO Commission on Intellectual Property Rights, Innovation and Public Health (CIPIH), http://www.who.int/intellectualproperty/report/en/
(18) Report of the WHO Consultative Expert Working Group on R&D Financing and Coordination (CEWG), (2012) http://www.who.int/phi/CEWG_Report_5_April_2012.pdf
(19) Universal Declaration of Human Rights (Article 27) http://www.ohchr.org/EN/UDHR/Documents/UDHR_Translations/eng.pdf; International Covenant on Economic, Social and Cultural Rights (Article 15, 1b) http://www.ohchr.org/Documents/ProfessionalInterest/cescr.pdf; see also Special Rapporteur reports: A/HRC/20/26; A/70/279
(20) ICESCR (Article 12); UN Committee on Economic, Social and Cultural Rights (General Comment 14)
(21) WHO (2015), Global Tuberculosis Report 2015 (page 1)
(22) Universal Declaration of Human Rights (Article 25); ICESCR (Article 12)
(23) WHO Constitution, (preamble, page 1) http://www.who.int/governance/eb/who_constitution_en.pdf
(24) UN Committee on Economic, Social and Cultural Rights (General Comment 14)
(25) Universal Declaration of Human Rights (Article 27); ICESCR (Article 15, 1b).
(26) World Trade Organisation, Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS) (Article 7) https://www.wto.org/english/docs_e/legal_e/27-trips.pdf
(27) UN, (A/HRC/20/26)
(28) UN, (A/70/279) http://daccess-dds-ny.un.org/doc/UNDOC/GEN/N15/243/83/PDF/N1524383.pdf?OpenElement
(29) WHO (2014), Regional Office for Europe, Summary Report on the nomination of Experts and the shortlisting of Health R&D Demonstration Projects http://www.who.int/phi/implementation/EURO_procedure_for_selection_of_demo_projects.pdf