Christine Årdal

International cooperation to improve access to and sustain effectiveness of antimicrobials

Securing access to effective antimicrobials is one of the greatest challenges today. Until now, efforts to address this issue have been isolated and uncoordinated, with little focus on sustainable and international solutions. Global collective action is necessary to improve access to life-saving antimicrobials, conserving them, and ensuring continued innovation. Access, conservation, and innovation are beneficial when achieved independently, but much more effective and sustainable if implemented in concert within and across countries. WHO alone will not be able to drive these actions. It will require a multisector response (including the health, agriculture, and veterinary sectors), global coordination, and financing mechanisms with sufficient mandates, authority, resources, and power. Fortunately, securing access to effective antimicrobials has finally gained a place on the global political agenda, and we call on policy makers to develop, endorse, and finance new global institutional arrangements that can ensure robust implementation and bold collective action.

An Open Source Business Model for Malaria

Greater investment is required in developing new drugs and vaccines against malaria in order to eradicate malaria. These precious funds must be carefully managed to achieve the greatest impact. We evaluate existing efforts to discover and develop new drugs and vaccines for malaria to determine how best malaria R&D can benefit from an enhanced open source approach and how such a business model may operate. We assess research articles, patents, clinical trials and conducted a smaller survey among malaria researchers. Our results demonstrate that the public and philanthropic sectors are financing and performing the majority of malaria drug/vaccine discovery and development, but are then restricting access through patents, ‘closed’ publications and hidden away physical specimens. This makes little sense since it is also the public and philanthropic sector that purchases the drugs and vaccines. We recommend that a more “open source” approach is taken by making the entire value chain more efficient through greater transparency which may lead to more extensive collaborations. This can, for example, be achieved by empowering an existing organization like the Medicines for Malaria Venture (MMV) to act as a clearing house for malaria-related data. The malaria researchers that we surveyed indicated that they would utilize such registry data to increase collaboration. Finally, we question the utility of publicly or philanthropically funded patents for malaria medicines, where little to no profits are available. Malaria R&D benefits from a publicly and philanthropically funded architecture, which starts with academic research institutions, product development partnerships, commercialization assistance through UNITAID and finally procurement through mechanisms like The Global Fund to Fight AIDS, Tuberculosis and Malaria and the U.S.’ President’s Malaria Initiative. We believe that a fresh look should be taken at the cost/benefit of patents particularly related to new malaria medicines and consider alternative incentives, like WHO prequalification.

To the G20: incentivising antibacterial research and development

www.thelancet.com/infection Published online July 6, 2017 http://dx.doi.org/10.1016/S1473-3099(17)30404-8 1 The antibiotic pipeline is insufficient. For example, only about five truly novel antibiotic classes are in clinical development for critical or high unmet public health needs defined by WHO. Given attrition rates, only two of these antibiotic classes are likely to receive regulatory approval during the next 7 years. The earlier, preclinicalphase pipeline is hard to assess, but might include more than a dozen novel antibiotics. However, their chances of success are even more remote than those currently in development, and are probably more than a decade away from being approved. Meanwhile, resistance rates to the world’s current stock of antibiotics are rising, not only threatening the ability to treat infections, but also jeopardising the ability of modern health-care to safely treat cancer and undertake many surgeries. Deliberate and coordinated action is needed now to ensure continuous availability of effective antibiotics. In 2016, the G20 committed to “unlock research and development into new and existing antimicrobials from a G20 value-added perspective”. DRIVE-AB, a 3-year research project financed by the European Union’s Innovative Medicines Initiative (IMI), is close to concluding its work on incentives and policies to stimulate innovation, sustainable use, and equitable availability of novel antibiotics to meet unmet public health needs. In this Comment, we summarise some of DRIVE-AB’s findings that are pertinent to the G20 commitments, including a market entry reward (MER). DRIVE-AB’s complete findings will be published and presented at the DRIVE-AB conference in Brussels on Sept 5–6, 2017. These include detailed findings and recommendations regarding new economic models, the societal value of antibiotics, forecasting the development of resistance, and responsible use measures. Incentives to stimulate antibacterial innovation can be grouped into two types: push incentives that pay for the research and development (R&D), and pull incentives that reward an outcome such as regulatory approval. Substantial investments are already occurring to push innovation, including grant financing—eg, the Biomedical Advanced Research and Development Authority, IMI, Joint Programming Initiative on Antimicrobial Resistance, the Horizon 2020 research programme, and most recently the Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator and the Global Antibiotic R&D Partnership, which acts as a virtual developer. These efforts are laudable, necessary, and must continue. They ensure that the pipeline is directed at public health needs. Yet the success of these initiatives in bringing novel antibiotics to market depends on continued private investment. Our stakeholder analyses identify that the willingness of companies and other private investors to invest in antibacterial R&D is primarily driven by anticipated market rewards—ie, the pull incentives. The traditional pull incentive is revenues from unitbased sales. Yet for new antibiotics, revenues alone might not be sufficient to encourage companies to invest in the development of new antibiotics. In clinical practice, novel antibiotics should be reserved for use against bacteria that are resistant to existing antibiotics. If infection prevention efforts are successful, such infections might be relatively rare, so sales volumes will be low. Therefore, new pull incentives are needed that effectively reward innovation and reduce revenues derived from sales volume—a so-called delinked model. Without an effective pull incentive, private sector investment will continue to decline, and the few remaining companies will leave antibacterial R&D, further diminishing innovation. To the G20: incentivising antibacterial research and development

An assessment of the future impact of alternative technologies on antibiotics markets

BackgroundThe increasing threat of antimicrobial resistance combined with the paucity of new classes of antibiotics represents a serious public health challenge. New treatment technologies could, in theory, have a significant impact on the future use of traditional antibiotics, be it by facilitating rational and responsible use or by product substitution in the existing antibiotics markets, including by reducing the incidence of bacterial infections through preventative approaches. The aim of this paper is to assess the potential of alternative technologies in reducing clinical use of and demand for antibiotics, and to briefly indicate which segments of the antibiotics market that might be impacted by these technologies.MethodsAn initial mapping exercise to identify the alternative technologies was followed by a review of relevant published and grey literature (n = 52). We also carried out stakeholder engagement activities by a round-table discussion with infectious disease specialists and a multi-criteria decision analysis exercise with pharmaceutical industry experts.ResultsTen alternative technologies were identified and analyzed for their potential impact on the antibiotics market. Of these, rapid point-of-care diagnostics, vaccines, fecal microbiota transplantation, and probiotics were considered to have a “high” or “medium” potential impact over a 10-20 year horizon. Therapeutic antibodies, antibiotic biomaterials, bacteriophages, antimicrobial nanoparticles, antimicrobial peptides, and anti-virulence materials were rated as having “low” potential impact.ConclusionDespite the apparent potential of the most promising alternative technologies to reduce demand, that reduction will likely only happen in limited segments of the antibiotics market or, in the case of preventing community acquired streptococcal infections by vaccination, in a low-price generics market segment. Thus, alternative technologies are not expected to represent any disincentive to antibiotics developers. Finally, it is unlikely that alternative technologies will displace the need for new classes, and sub-classes, of antibiotics in the short and medium terms.

Market watch: Innovation in the preclinical antibiotic pipeline

Antibiotic resistance is high on the political agenda and improving the antibiotic R&D pipeline is one of the major action points. The Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator (CARB-X) supports antibacterial projects through early preclinical development, with a 5-year budget totalling US

A Grant Framework as a Push Incentive to Stimulate Research and Development of New Antibiotics

455 million (Nat. Rev. Drug Discov. 15, 589–590; 2016). Since its inception in July 2016, 368 applications from around the world have been submitted. This pool of information provides a reasonable approximation of global preclinical antibiotic R&D activities and was used for this analysis. Of 368 submitted projects, we excluded funding requests for diagnostics and out-of-scope applications, leaving 254 applications for analysis (FIG. 1). More than 50 small-molecule preclinical projects among the CARB-X submissions focused on at least one of the critical priority pathogens on the WHO global priority list that was recently published to guide antibiotic R&D, which are all extensively drug-resistant Gram-negative bacteria. The small molecules being investigated by these projects belong to new chemical and/or functional classes with no anticipated cross-resistance to existing classes (FIG. 1a). These projects exhibit considerable diversity, with several clusters (FIG. 1b) as well as a large group of projects classified as ‘other’. The largest cluster are membrane-targeting agents, including compounds modelled on natural antimicrobial peptides. There is also a substantial cluster of agents that inhibit M A R K E T WAT C H

Should Antibiotics Be Controlled Medicines? Lessons from the Controlled Drug Regimen

Antibiotic research and development (R&D) has failed to produce innovative antibiotics in the past two decades, which is due to both scientific and economic factors. We reviewed national and international funding agencies and critically assessed current grant funding mechanisms. Finally, we propose four complementary grant-funding incentives aimed to help developers along the R&D pipeline. Equally important objective of these incentives is to address some of the known R&D risks and bottlenecks.

Designing a Delinked Incentive for Critical Antibiotics: Lessons from Norway:

This study aimed to identify the antibiotic-relevant lessons from the controlled drug regimen for narcotics. Whereas several elements of the United Nations Single Convention on Narcotic Drugs (1961) could be advantageous for antibiotics, we doubt that an international legally binding agreement for controlling antibiotic consumption would be any more effective than implementing stewardship measures through national AMR plans.

Linking sustainable use policies to novel economic incentives to stimulate antibiotic research and development

No country has yet implemented a pilot to ensure access to or the innovation of new antibiotics for multi-drug infections. A team from national health agencies in Norway, with the support of the Innovative Medicine Initiative-funded project DRIVE-AB, designed a model suitable for the national context, including the selection of the antibiotics, the potential value, and the operational model.

Financing and collaboration on research and development for nodding syndrome.

There is now global recognition that antibiotic resistance is an emerging public health threat. Policy initiatives are underway to provide concrete suggestions for overcoming important obstacles in the fight against antibiotic resistance, like the alarming current paucity of antibacterial innovation. New economic models are needed as incentives for the discovery and development of novel antibacterial therapies especially for infections with too few patients today to justify private sector research and development (R&D) investments. These economic models should focus on rewarding the innovation, not the consumption of the antibiotic since sustainable use policies will reduce selection pressure and slow the emergence of resistance. To effectively stimulate greater innovation, the size of the reward must be commensurate with revenues from other therapeutic areas, estimated at about a billion dollar total pay-out. Otherwise R&D investment will continue to move away from antibiotics to areas where returns are more attractive. A potential sizeable public investment, if implemented, must be protected to ensure that the resulting antibiotics have a lengthy and positive impact on human health. Therefore, public investments in innovation should be bound to sustainable use policies, i.e., policies targeted at a range of actors to ensure the preservation of the novel antibiotics. These policies would be targeted not only at the innovating pharmaceutical companies in exchange for the reward payments, but also at governments in countries which receive the novel antibiotics at reasonable prices due to the reward payment. This article provides some suggestions of sustainable use policies in order to initiate the discussions. These are built on planned policies in the US, EU, WHO and have been expanded to address One Health and environmental aspects to form One World approaches. While further discussion and analyses are needed, it is likely that strong sustainable use policies will help to protect the sizeable public health investments.