Every time a newly discovered molecule or preclinical drug makes the headlines as a “cure for drug resistant infections,” we risk people thinking that the problem has been solved
Winning the “battle” against drug resistant infections will require new antibiotics, as well as public and professional behavioural change, better diagnostics, hygiene practices, and vaccines—all to either reduce unnecessary antibiotic use or to limit the spread of infections. No single new antibiotic is going to completely solve the problem of resistant infections, nor are most of the antibiotics in the early stages of development likely to make it to market.
Yet researchers often tout early stage successes in antibiotic development to the media as being potential game changers in preventing resistant infections. These statements are often misguided. Furthermore, they may undermine wider policy efforts to improve the research and development system for antibiotics because they create the impression that our current research system is adequate.
Discovering, developing, and successfully licensing a new antibiotic typically costs in excess of one billion US dollars and tends to take more than a decade. While this does not differ greatly from other areas of medicine in cost or time, unlike other drugs, antibiotics become less effective the more they are used, pushing public health officials to protect the newest and most valuable antibiotics. This means that the volume of sales that a useful new antibiotic can achieve is comparatively very low, which makes antibiotic development an unattractive investment for many companies. This is worrying, both because rates of antimicrobial resistance (AMR) and drug resistant infections are rising globally, and because the long lag between early stage research and a successfully launched new antibiotic means that we ought to invest now so that we don’t face a much larger medical crisis in the future.
Lord Jim O’Neill’s Review on Antimicrobial Resistance, which we both served on, argued that the large negative externality created by using antibiotics justified state intervention in order to reward the development of new drugs. Its proposed strategies for achieving this included raising the media profile of this area and engaging with policy makers in order to raise public awareness of the huge public health and economic costs of inaction. We believe that this is in the interests both of those working to develop new antibiotics and of society as a whole.
We are encouraged that since publication of the review’s final report in May 2016 there have been substantial efforts in the G20, World Economic Forum, the Organisation for Economic Co-operation and Development (OECD), the World Bank, and elsewhere to reform the antibiotics market and to explore new reimbursement models. We are enthusiastic about new “push” incentive schemes, such as CARB-X, to fund early stage antibiotic and diagnostics research, but “pull” incentives for new marketed drugs, such as the “market entry rewards” favoured by the O’Neill review, are also needed.
However, sometimes the individuals in a group each have personal incentives that force them to behave in a way that can be detrimental to the group as a whole, in what economists call a “tragedy of the commons.” To illustrate this concept using commercial fishing as an example, it is in every fisherman’s interest that overfishing is limited so that fish stocks don’t run out. However, each independent fisherman wants to sell as many fish as possible now. By doing so, they gain short term benefit from the fish they catch and pay only a tiny fraction of the longer term overfishing problem to which they are contributing. The collective behaviour of individuals is therefore suboptimal, which is why governments often step in to create fishing quotas or rules. Similarly, while every researcher working on new antibiotics gains from an improved public perception that AMR and drug resistant infections are a major problem, it is also in their individual interests when raising funding to claim that their new drug is likely to solve (part of) this problem.
In order to fix the structural market problems that are holding back investment for new antibiotics, we need to engage policy makers. This means ensuring that they, the voting public, and the media at large understand the costs of inaction and are given realistic information about new developments. Every time a newly discovered molecule or preclinical drug makes the headlines as a “cure for drug resistant infections”—often as a strategy to lever further research funding—we risk people thinking that the problem has been (or will soon be) solved without changes to the market structure. This behaviour may undermine efforts to reform the antibiotic market and will eventually affect us all.
In particular we are concerned that few non-experts will ever read beyond headlines of new “super antibiotics,” and so will not appreciate the limitations. New antimicrobial discoveries require independent and balanced perspectives that convey not only the potential promise, but also the far greater scope for failure. These should be written by or with expert scientists (for example, Piddock 2017). However, all too often, headlines overestimate the likely chances of success.
Although it is often difficult for researchers to raise funding for antibiotic discovery programmes, greater consideration needs to be given to the potential negative effects that high publicity messaging may cause. Unlike in our fishing example, governments cannot step in to regulate the hyping up of scientific results and discoveries.
At the very least, researchers and journalists need to be more honest in their press releases and news stories, and should be clear that any drug that has not yet gone into humans has about a 2% chance of making it through clinical development and licensing to market. If we are realistic, while all new antibiotic discoveries have potential, it’s unlikely that any single new compound will provide—or sadly even contribute to—the solution we need.
Anthony McDonnell is a researcher at the London School of Economics working to understand the economic impact of malaria eradication in India. Prior to this Anthony headed an international working group on clinical trial networks and he was head of economic research for the UK’s Independent Review on Antimicrobial Resistance, chaired by Jim O’Neill.
Competing interests: AM is currently working at the Wellcome Trust. Nothing further to declare.
Neil Woodford is head of the antimicrobial resistance and healthcare associated infections (AMRHAI) reference unit at Public Health England. His unit is a WHO collaborating centre. Neil is a visiting professor at Imperial College London where he also did his doctoral studies on Neisseria gonorrhoeae, and an honorary professor at University College London and at the University of KwaZulu-Natal (South Africa). He sits on many national and international committees relating to antimicrobial resistance, and served as the scientific adviser to O’Neill’s Review on Antimicrobial Resistance (2014-16).
Competing interests: NW has none to declare. However, PHE’s AMRHAI reference unit has received financial support for conference attendance, lectures, research projects, or contracted evaluations from numerous sources, including: Accelerate Diagnostics, Achaogen Inc, Allecra Therapeutics, Amplex, AstraZeneca UK Ltd, AusDiagnostics, Basilea Pharmaceutica, Becton Dickinson Diagnostics, bioMérieux, Bio-Rad Laboratories, the BSAC, Cepheid, Check-Points B.V., Cubist Pharmaceuticals, Department of Health, Enigma Diagnostics, Food Standards Agency, GlaxoSmithKline Services Ltd, Helperby Therapeutics, Henry Stewart Talks, IHMA Ltd, Innovate UK, Kalidex Pharmaceuticals, Melinta Therapeutics, Merck Sharpe & Dohme Corp, Meiji Seika Pharma Co., Ltd, Mobidiag, Momentum Biosciences Ltd, Neem Biotech, NIHR, Nordic Pharma Ltd, Norgine Pharmaceuticals, Rempex Pharmaceuticals Ltd, Roche, Rokitan Ltd, Smith & Nephew UK Ltd, Shionogi & Co. Ltd, Trius Therapeutics, VenatoRx Pharmaceuticals, and Wockhardt Ltd.
Sertkaya A, Birkenbach A, Berlind A, Eyraud J. Examination of clinical trial costs and barriers for drug development. Report for the US Department of Health and Human Services, Office of the Assistant Secretary for Planning and Evaluation, Washington, DC. 2014;1-92. https://aspe.hhs.gov/report/examination-clinical-trial-costs-and-barriers-drug-development
Review on Antimicrobial Resistance. Tackling drug-resistant infections globally: final report and recommendations. 2016. http://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf
Antimicrobial Resistance: Policy Insights. OECD. 2016. https://www.oecd.org/health/health-systems/AMR-Policy-Insights-November2016.pdf
Adeyi OO, Baris E, Jonas OB, et al. Drug-resistant infections: a threat to our economic future. World Bank Group, Washington, DC. 2017;Vol. 2. http://documents.worldbank.org/curated/en/323311493396993758/final-report
Outterson K, Rex J, Jinks T, et al. Accelerating global innovation to address antibacterial resistance: introducing CARB-X. Nature reviews Drug Discovery. 2016;15:589-590. doi:10.1038/nrd.2016.155. https://www.nature.com/articles/nrd.2016.155
Simpkin VL, Renwick MJ, Kelly R, Mossialos E. Incentivising innovation in antibiotic drug discovery and development: progress, challenges and next steps. The Journal of antibiotics. 2017;70:1087-1096. doi:10.1038/ja.2017.124. https://www.nature.com/articles/ja2017124
Piddock LJV. Teixobactin, the first of a new class of antibiotics discovered by iChip technology? Journal of Antimicrobial Chemotherapy. 2015;70:2679-2680. doi:10.1093/jac/dkv175. https://academic.oup.com/jac/article/70/10/2679/830198