The problem: investing in new antibiotics doesn’t pay off
One of the biggest challenges of our age is the looming threat of antimicrobial resistance (AMR). In the past few years, it has become a high-profile policy priority for governments and global institutions, thanks to many voices sounding the alarm on the implications of an antibiotics-free future. But despite the well-publicised threat, few new antibiotics are in the pipeline. The reason development has stalled has as much to do with economics as pharmacology; the pharmaceutical industry has no incentive to develop drugs that are expected to be used only rarely, assuming efforts in infection prevention and antimicrobial stewardship are successful. The purpose of DRIVE-AB was to create evidence for policymakers on new ways to stimulate drug and biotech companies to invest in new antibiotics in a way that’s consistent with efforts to responsibly limit their use.
Getting the terminology right, predicting resistance, estimating value
First off, the project partners agreed on some basic definitions. While we know that the overuse of antibiotic drugs is the reason for resistance, there’s not a whole lot of agreement on what “responsible” use looks like. DRIVE-AB project partners looked into the available literature and rated the varying definitions, ultimately settling on a description for responsible use that, they posit, should form the basis of any model that tackles the new-drugs-versus-sustainable-consumption solutions.
They then developed models created to predict the spread of antibiotic resistance, intended to help health systems and drug companies make decisions about where the money and effort needs to go. The project partners also described – and assigned value amounts to – the consequences for the different people affected by AMR; what is the cost to a patient, a hospital, society as a whole of untreatable infections? They did the same type of quantification in the reverse: what is it worth to society to have a new antibiotic that works?
The fire extinguisher analogy: buying protection from future fires
A key finding from DRIVE-AB is that antibiotics are very valuable to society as preparedness for future drug resistance. A useful analogy is fire suppression equipment: we invest in the equipment while hoping that the actual number of fires is zero. To apply the same thinking to antibiotics calls for dramatic changes in how societies pay for them. It would require delinking revenues to the company from the number of pills sold. Antibiotics should be reimbursed based on their value to society, not the volume of patients being treated today. Those that treat Gram-negative infections, for example, are considered more valuable because these bacteria are more dangerous.
The outcome: a rethink of antibiotics’ true value
They key takeaway is that new economic models should be based on this “true value” of the new drugs. DRIVE-AB quantitatively modelled the most promising incentive systems in terms of profitability and benefit to the public, covering everything from basic science to patient treatment. They did an in-depth analysis of dozens of ideas in the policy literature, and settled on four incentives that can be considered best suited to fill the antibacterial pipeline and keep them available. The project simulated the impact of market entry rewards, which are rewards or prizes for bringing new antibiotics to the market, and found that a global reward of USD 1 billion (approx. EUR 0.9 billion), based on certain assumptions, would result in a steady supply of more innovative antibiotics.
DRIVE-AB also recommended a long-term supply continuity model for important but rarely-used antibiotics. They recommend a country or group of countries would agree to annual payments to one or more manufacturers to ensure predictable supply, and a number of sustainable use obligations for developers.
Conflicting perspectives: seeing it from the other side
The project has had immense influence; anyone involved in AMR policy is never far removed from the highly networked DRIVE-AB community. The project only served to further expand and solidify this network. Its 16 public-sector partners and seven pharmaceutical companies operated as equal partners and spent three years meeting in various fora. While the motivations of the public and private partners didn’t always align, it was a great opportunity for each camp to see the issue of antimicrobial research from the other perspective. The partners were able to work together as equals to hypothesise a mutually beneficial investment environment that achieves a goal that is common to all sides. Such cross-over collaborations is one of the great potential advantages of participating a public-private funding vehicle like IMI.
Of the 12 policy recommendations, six are now being fully or partially implemented, say the project partners, including as part of the UK’s AMR review and an AMR report carried out by Boston Consultancy Group on behalf of the German federal government. The recommendations have also influenced the policies of the World Health Organisation, the Joint Action on Antimicrobial Resistance and Healthcare-Associated Infections (EUJAMRAI), and the Global AMR R&D Hub.
Although not a delinked model, the US government has recently taken an initial step to change the reimbursement pattern for new antibiotics used in the hospital, and the United Kingdom recently announced a pilot project looking at a delinked model. Legislation that could create such a model is also being considered in the United States. We can expect to see more and more policymakers adopt, or take inspiration from, the work done through the DRIVE-AB project.
Achievements & News
A mix of economic drivers and incentives is needed to stimulate antibiotic development, according to the final report of IMI’s DRIVE-AB project. The report, based on input from diverse stakeholders, highlights four incentives that would be the most effective in stimulating the antibiotic pipeline while also ensuring that critical antibiotics are used sustainably and are accessible to all who need them. ###The incentives picked out by the report are:
- Grants: non-repayable funds for R&D given to academic institutions, companies and others;
- Pipeline coordinators: governmental or non-profit organizations that closely track the antibiotic pipeline (or subsets thereof), identify gaps, and actively support R&D projects both financially and technically to fill these gaps;
- Market entry rewards: a series of financial payments to an antibiotic developer for successfully achieving regulatory approval for an antibiotic that meets specific predefined criteria to address a defined public health need, with obligations for sustainable use, equitable availability and supply;
- Long-term supply continuity model: a delinked payment to create a predictable supply of important generic antibiotics.
All of the recommended incentives would include mandatory provisions for equitable access and sustainable use in order to ensure these critical medicines are available to patients who need them globally, and remain effective over time. ‘The models are meant to be complementary and don’t operate in isolation. Instead, they’re designed to form an ecosystem that maximizes R&D while ensuring access and sustainable use of new antibiotics over time,’ said Christine Årdal, DRIVE-AB partner and Senior Advisor at the Norwegian Institute of Public Health.
Read the project’s press release
New antibiotics will have to be used sparingly to preserve their efficacy. IMI’s DRIVE-AB focuses on ways to stimulate their development. A combination of incentives is required, the researchers note. In particular, they highlight the need to ‘delink’ the revenue generated by new drugs from the quantities sold. To do so, they propose a combination of push and pull mechanisms. ### Priority grants could, for example, be used to get the innovation process moving. A system of rewards for market entry could be set up to encourage its completion. This type of approach would contrast with the business model traditionally applied to drugs, where income depends on the volume of sales.
DRIVE-AB ends in December 2017, and the partners are preparing to publish their final report along with detailed recommendations. ‘We have aimed to encourage a balance between innovation and responsible use,’ says Nicole Mahoney of Merck Sharp & Dohme (MSD), one of the project partners. Policymakers and other stakeholders could find ample inspiration in DRIVE-AB’s conclusions. As a first step, the project’s findings might, for instance, feed into pilot studies at national levels, says Mahoney. ‘We may well see individual countries trialling some of these ideas and setting up reward mechanisms that work within their local context,’ she concludes.
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'Revitalising the Antibiotic Pipeline', the final conference of IMI’s DRIVE-AB project, will be held in Brussels, Belgium on 5-6 September 2017. The event will bring together high-level policy makers, regulatory and public health experts, economists and representatives of pharmaceutical companies, the medical community and civil society to discuss DRIVE-AB’s results and recommendations and suggest solutions for their implementation around the globe.###Some confirmed faculty members include representatives from the World Health Organization, the European Investment Bank, the Biomedical Advanced Research and Development Authority, the Drugs for Neglected Diseases initiative, and the EU Joint Programming Initiative for AMR. In addition, over 20 posters on DRIVE-AB research and results will be showcased at the conference. Spaces are filling up fast - if you are interested in attending the conference, register your interest with Victoria Wells at VWells@BSAC.org.uk.
IMI project DRIVE-AB is working to define new, alternative economic models for antibiotic development that balance the need to reward those who develop new antibiotics with the need to use new antibiotics only when absolutely necessary. Now the project has shared its preliminary ideas with 180 high-level experts at a conference in Amsterdam, the Netherlands on 2 June. ###Some key points arising from discussions at the event include:
- Hospital stewardship programmes and antibiotic regulation are either lacking or insufficient in many parts of the world.
- Efforts to address antibiotic resistance should be coordinated globally.
- Reward models for antibiotics should align with sustainable use policies and delink the volume of sales from return on investment.
- New reward models should be piloted in appropriate settings as soon as possible, with support from pharmaceutical companies.
- Innovation and sustainable use are only part of the equation for addressing antibiotic resistance. Infection prevention and control, vaccine use and a One Health approach are necessary as well.
- There is a need for coordinated global public investment, which should direct antibiotic research and development to meet public health needs that are defined by a global body.
IMI’s DRIVE-AB project will hold a high-level conference entitled ‘Stimulating innovation, sustainable use and global access to antibiotics’ on 2 June in Amsterdam, the Netherlands. The goal of the event is to bring together policy makers, regulatory and public health experts, and economists to identify and evaluate reward models that are feasible, practical and can be implemented globally.### At the event, DRIVE-AB will present the preliminary results of its research and seek feedback from stakeholders regarding feasibility and implementation of research and development (R&D) incentive policies. The conference also seeks to determine how on-going European and international initiatives addressing antimicrobial resistance can complement each other, and to identify opportunities for DRIVE-AB to interact with other initiatives. If you would like to apply for a space at the conference, contact DRIVE-AB Communications Officer Victoria Wells at firstname.lastname@example.org.
The Alliance for the Prudent Use of Antibiotics (APUA) has named Professor Kevin Outterson of Boston University School of Law and Boston University School of Public Health as the recipient of its 2015 leadership award.### Professor Outterson is a partner in the DRIVE-AB, which is working on developing new economic models that simultaneously incentivise antibiotic development while promoting the responsible use of antibiotics. ‘We recognise Professor Outterson as a thought leader in the worldwide effort to contain antibiotic resistance,’ said APUA President Stuart B. Levy. ‘His intellectual commitment to the economic realities of developing new drugs that affect the global aspects and consequences of antibacterial resistance alter our thinking about answers to these complex problems.’ In DRIVE-AB, Professor Outterson contributes to the project’s activities on the creation and testing of new economic models.
A 30% drop in the efficacy of antibiotics could result in an additional 6 300 deaths per year in the US alone among people who undergo common surgeries and chemotherapy treatments. This is the stark finding of a study, published in the Lancet Infectious Diseases, by the IMI project DRIVE-AB.### Patients who undergo surgery or immune-system suppressing chemotherapy are routinely given antibiotics to prevent infections. The DRIVE-AB team analysed the number of additional infections and deaths that would occur if these antibiotics were less effective. They focused their analysis on the 10 most common surgeries (e.g. caesarean sections, prostate biopsies, hip replacements, and appendix removals) as well as on chemotherapy treatments that suppress the immune system. They found that a 30% reduction in the efficacy of these preventive antibiotic treatments could result in 120 000 additional infections and 6 300 deaths. ‘Most of us will take antibiotics at some point in our lives and everyone should be mindful of the fact that resistance is a potential problem if we are going in for minor surgery, hip or knee replacement, transplant or chemotherapy,’ said lead author Ramanan Laxminarayan of the University of Strathclyde, the Center for Disease Dynamics, Economics & Policy, and Princeton University. ‘Our findings are likely to hold true in many other developed countries, given the common use of surgical procedures.’ The researchers conclude by noting that clinical studies are needed to determine how recommendations on the use of antibiotics should be modified as drug resistance rises.
Antimicrobial resistance project DRIVE-AB is looking for stakeholders willing to provide input on its reports and recommendations. Launched in 2014, the project’s goal is to develop economic models that would simultaneously incentivise the development of new antibiotics while reconciling this with the need to use new antibiotics wisely.### The project is keen to gather input from a broad range of stakeholders to ensure their findings are as robust as possible. Groups interested in becoming stakeholders should fill in the form on the DRIVE-AB website. The project has already attracted a number of high profile stakeholders including international institutions like the World Bank and European Medicines Agency, as well as clinical societies and universities. DRIVE-AB was also instrumental in the creation of the BEAM Alliance (‘Biotechs from Europe innovating in Anti-Microbial Resistance’), which is working to improve the regulatory, investment, and commercial environments in Europe for research, development, approval and market viability of new products combating antimicrobial resistance.
ParticipantsShow participants on map
- Astellas Pharma Europe LTD, Chertsey, United Kingdom
- Astrazeneca AB, Södertälje, Sweden
- F. Hoffmann-La Roche AG, Basel, Switzerland
- Glaxosmithkline Research And Development LTD., Brentford, Middlesex, United Kingdom
- Merck Sharp & Dohme Corp, Whitehouse Station, New Jersey, United States
- Pfizer Limited, Sandwich, Kent , United Kingdom
- Sanofi-Aventis Recherche & Developpement, Chilly Mazarin, France
Universities, research organisations, public bodies, non-profit groups
- British Society for Antimicrobial Chemotherapy, Birmingham, United Kingdom
- Eberhard Karls Universitaet Tuebingen, Tuebingen, Germany
- Folkehelseinstituttet, Oslo, Norway
- London School Of Economics And Political Science, London, United Kingdom
- Ruprecht-Karls-Universitaet Heidelberg, Heidelberg, Germany
- Stichting Radboud Universiteit, Nijmegen, Netherlands
- Sveuciliste U Rijeci, Medicinski Fakultet, Rijeka, Croatia
- The Foundation For Medical Research Infrastructural Development And Health Services Next To The Medical Center Tel Aviv, Tel Aviv, Israel
- The Royal Institute Of International Affairs, London, United Kingdom
- Universite De Geneve, Genève 4, Switzerland
- Universite De Lorraine, Nancy Cedex, France
- Universiteit Antwerpen, Antwerp, Belgium
- University Of Strathclyde, Glasgow, United Kingdom
- Uppsala Universitet, Uppsala, Sweden
- Wageningen University, Wageningen, Netherlands
Small and medium-sized enterprises (SMEs)
- Ursula Theuretzbacher, Vienna, Austria
|Name||IHI funding in €|
|British Society for Antimicrobial Chemotherapy||276 662|
|Eberhard Karls Universitaet Tuebingen||276 703|
|London School Of Economics And Political Science||91 078|
|Ruprecht-Karls-Universitaet Heidelberg||56 817|
|Stichting Radboud Universiteit||280 445|
|Sveuciliste U Rijeci, Medicinski Fakultet||24 300|
|The Foundation For Medical Research Infrastructural Development And Health Services Next To The Medical Center Tel Aviv||394 955|
|The Royal Institute Of International Affairs||229 839|
|Universite De Geneve||1 670 756|
|Universite De Lorraine||130 403|
|Universiteit Antwerpen||74 770|
|University Of Strathclyde||572 380|
|Uppsala Universitet||933 080|
|Ursula Theuretzbacher||351 640|
|Wageningen University||37 059|
|Total Cost||6 299 987|