by Matthew J Renwick, Victoria Simpkin and Elias Mossialos
Antimicrobial resistance (AMR) is currently responsible for over 700,000 deaths annually around the world. AMR mortality is predicted to rise exponentially to above 10 million deaths per year by 2050. The global economic cost of such a rise in mortality and morbidity is estimated to be $100 trillion.
Lack of innovation
Development of novel antibiotics, alternative therapies and diagnostics tools is critical to the global fight against AMR. However, the pipeline for antibiotics and related products is limited. Since 2000, only five novel classes of antibiotics have been marketed; none of these target deadly and highly resistant gram-negative bacteria. The total number of submitted antibiotic patents has declined by 34.8% between 2007 and 2012.
A partial picture of the EU/US antibiotic pipeline shows that there are at least 19 antibiotic products including alternative therapies in clinical development Phase I, 27 in Phase II and 6 in Phase III. Despite 52 products in the pipeline, only one is a systemic antibiotic with a novel mechanism of action and it is limited to a specific bacteria. A development timeline for these drugs is unknown.
Tracking return on investment in antibiotics
A look at US and EU public funding of antibiotic R&D demonstrates that Europe has invested ~€147 million annually between 2007–13 and the US has invested $260 million (€234 million) in 2015. Having been stable since 2010, US investment in antibiotic R&D is expected to grow to $413 million (€382 million) in 2016. However, it is unclear how the differences in funding have affected outcomes in the pipeline, which highlights the need for ongoing assessment of public return on investment in antibiotics.
Moreover, European and US governments appear to have only limited means of eventually recapturing these large investments should their funding result in marketable antibiotics. Regarding private investment, global venture capital in antimicrobial R&D has declined by 28% between the two five year periods of 2004–08 and 2009–13. Venture capital investment in gram-negative antimicrobials has increased by 51% during these two periods, but it still comprises only 12% of total venture capital investment in antimicrobials. The amount of internal capital invested by developers into their own antibiotic projects is unknown.
A proliferation of incentives
In response to this growing crisis, there has been a proliferation of initiatives to stimulate the antibiotic development pipeline. In total, there are 58 active R&D initiatives and sub-initiatives at global, EU and national levels (UK, France, Germany, Netherlands, Sweden, US and Canada) that directly incentivise antibiotic R&D. Additionally, there are nine active initiatives that indirectly support antibiotic R&D by coordinating strategic actions on AMR and seven initiatives that are either proposed or in preliminary stages of implementation.
The antibiotic R&D initiative environment is now crowded. There is room for improved coordination both between and within initiatives. Many initiatives are founded on various models of partnership that improve the possibilities for stakeholder collaboration but further complicate coordination efforts. A lack of coherence throughout R&D initiatives risks muddling priorities, duplicating efforts and missing synergistic opportunities.
Overuse of push incentives
Most initiatives improve the economic value of antibiotic R&D, but there is a heavy imbalance towards the use of push incentive tools. Of the active initiatives, 76% use only push mechanisms, 5% use only outcome-based pull mechanisms, 5% use lego-regulatory policies and 13% only coordinate AMR action and provide no form of R&D incentive. Only one initiative, the US BARDA, has the capacity to use a hybrid push-pull approach to incentivisation. The top three incentives are: direct project funding, research collaborations and research grants and fellowships. The vast majority of funding flows through push mechanisms of incentivisation.
Due to this push/pull imbalance, there is an unequal distribution of initiatives across the antibiotic value chain that favours basic research and early drug discovery phases. In addition, R&D initiatives primarily assist academic institutions and large pharmaceutical companies. SMEs are lacking support and often struggle to reach the clinical phases of development and market approval. Taxation policies that can be tailored to support SMEs developing antibiotics do not appear to be commonly used.
At the end of the antibiotic value chain, commercialization-focused pull incentives that are missing or are underutilized include end prizes/competitions and value-based pricing and reimbursement. Moreover, the EMA and FDA are using regulatory tools to facilitate antibiotic market authorisation. There is room for further harmonisation and cooperation between the EMA and FDA, as well as other drug regulatory agencies.
Public health perspective
Finally, from a public health perspective, antibiotic stewardship and patient access goals are poorly integrated into the current set of R&D initiatives. Many initiatives have not explicitly linked their incentives to high-priority medical needs in infectious disease.
Based on the key findings outlined above, LSE researchers put forward 16 recommendations which are set out in a report commissioned by the Dutch Government as part of its 2016 presidency of the European Union. The recommendations call for a coordinated One Health – One Europe – One World Framework for antibiotic drug discovery and development.
Renwick MJ, Simpkin V, Mossialos E (2016) Targeting Innovation in Antibiotic Drug Discovery and Development: The need for a One Health – One Europe – One World Framework, World Health Organisation.
This publication, commissioned by the Dutch Government, provided a platform for discussion among European Ministers of Health and Ministers of Agriculture during the 2016 Ministerial Conference on AMR. It is a follow up to a 2010 report commissioned by the Swedish government to examine incentive mechanisms for encouraging antibiotic development. The 2010 report formed the basis for an urgent request by the EU Council for action and sparked the formation of the critical ‘transatlantic taskforce’ (TATFAR): the first major international collaboration to tackle antibiotic resistance. Recommendations from the work served as the foundation for an EU-level public/private partnership and for US regulatory reform.
About the authors
Matthew J Renwick is Research Associate in Health Policy and Economics within LSE Health.
Victoria Simpkin is Research Associate in Health Policy within LSE Health.
Elias Mossialos is Brian Abel-Smith Professor of Health Policy and Director of LSE Health at the LSE. He is also Professor of Health Policy and Management at the Institute of Global Health Innovation, Imperial College London, and Co-Director of the European Observatory on Health Systems and Policies.