Making Use of Existing International Legal Mechanisms to Manage the Global Antimicrobial Commons: Identifying Legal Hooks and Institutional Mandates

Banning the manufacture, sale and export of substandard and falsified drugs is a prime opportunity for addressing AMR access concerns through international law. These substandard and falsified drugs are a growing global problem that can cause morbidity and mortality. Substandard drugs have not passed the usual standard and quality testing protocols and include falsified medicines that have been deliberately mislabeled with respect to their origin or contents [9]. A specific ban on such drugs might entail regulations on trade through the WTO’s Agreement on Technical Barriers to Trade (TBT) that require and ensure monitoring and compliance with rigorous quality assurance standards for antimicrobials. Similarly, the International Convention on the Harmonized Commodity Description and Coding System (HCDCS), with its focus on customs, could enforce compliance with these quality standards at the time of import and export. Finally, the WHO, FAO and OIE could support efforts to end the manufacturing and sale of these products through increased surveillance and education with regards to the harms associated with these products.

Another way to improve access to safe and effective medicine is through patent licensing [15]. Under the WTO's Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), governments can allow someone besides the patent holder (including the government itself) to produce a patent-protected product or use a patent-protected process for their domestic market. In normal circumstances, governments can attempt to obtain a voluntary license, which is a voluntary arrangement between the patent holder and government. In the event where a voluntary agreement cannot be reached, governments can issue a compulsory license which permits them to license the patent without the permission of the patent holder, provided that they first attempted to obtain a voluntary license. In extenuating circumstances, like in settings without the domestic capability of manufacturing high quality medicines, governments can issue a compulsory license of a patent and arrange for manufacturers in other countries to make the product for them, again provided that they first attempted to obtain a voluntary agreement [27]. These mechanisms, already authorized by international trade law, can increase global accessibility of antimicrobials. While licensing is an effective way to procure drugs at a low cost, it requires additional action to offset its potentially disruptive impact on innovation. In order to balance the tension between affordable drugs today and investment by the pharmaceutical industry in new drugs for the future, licensing must be paired with creative funding mechanisms such as prizes for newly developed technologies or a global fund to compensate patent holders when governments need to license antimicrobials.

International law could be a powerful tool to address the continuing rise of non-human antimicrobial use. A ban on non-therapeutic antimicrobial use through the FAO, or by employing regulations on trade through the SPS, could substantially enhance global antimicrobial stewardship. Either mechanism could include a minimum requirement of a universal ban of antimicrobial growth promotion and could also require parties to phase out prophylactic and metaphylactic non-human use of all antimicrobials by a certain year, such as 2030. Although the impact on human health remains imprecise, the non-human use of antimicrobials vastly exceeds global human use and has historically repeatedly selected for resistance factors that have impacted human health [10, 11, 22]. Protecting human health and acknowledging the One Health dimensions of AMR entails a stringent reduction of non-essential antimicrobial usage in global food production and major improvements in antibiotic stewardship in human health and the environment. Similarly, revisions could be made to the IHR or TRIPS to prospectively, automatically and strictly limit any new class of antimicrobials to human use only, until a designated international organization like the WHO, FAO or OIE has determined that its non-human use is safe for humans. Other measures will also help reduce non-human antimicrobial usage. Bans on the use of antimicrobials for animal growth promotion in agriculture have already been enacted in the EU, US, and other countries. Further restrictions on the use of critically important antimicrobials to treat entire herds (“metaphylaxis”) or medicate animals before infections are present (“prophylaxis”) were agreed by the European Parliament in 2018 [3]. Both growth promoter bans and restrictions on meta- and prophylaxis are designed to preserve antimicrobial effectiveness by limiting their non-human use and prioritizing essential therapeutic usage among those humans and animals who really need them.

Revisions to the TBT, SPS, and IHR could also be made to promote appropriate antimicrobial use such as by banning the commercial advertisement, marketing, and sales promotion of antimicrobials. These international efforts could reduce misinformation about antimicrobial effectiveness, dampen the transnational spread of this misinformation through social media, and strengthen efforts to curb the substantial international grey and black markets supplying substandard and falsified antimicrobials.

Beyond legal hooks, the mandates of various international organizations with the power to create international laws could be used to promote conservation goals. A WHO treaty could start by protecting human health and end with a call to transition away from using critically important antimicrobials in agriculture, and an FAO treaty could start with a call to transition away from critically important antimicrobials and end with a focus on developing, promoting, and supporting sustainable agricultural practices. Such treaties might emanate from Article 19 or 21 of the WHO’s constitution and Article 14 of the FAO’s constitution respectively, engage with WHO’s AWaRe framework, create provisions to limit the agricultural use of critically important antimicrobials for human health, and set standards to protect any new antimicrobials for future human health needs. In addition to being feasible within the existing legal mandates of the WHO and FAO, at least one large pharmaceutical company has committed not to license new antimicrobials for animal use [6], demonstrating there may be support for such rules from unexpected places.

A third possible avenue could be to strengthen surveillance and data sharing by adopting new legally binding regulations with existing institutional powers. New international standards are also required to standardize antimicrobial usage data collection, which should include statutory national reporting requirements of domestic and international sales data by commercial antimicrobial producers and distributors. A global surveillance infrastructure has to be politically neutral, transparent, and overseen by appropriate technical organizations. Ultimately these data must be gathered in a way that elicits trust. To avoid underreporting and geographic biases, the international community will probably have to establish and finance an integrated network of independent AMR reference laboratories around the world. At present there are a limited number of countries participating in WHO’s GLASS program as a result of data sharing concerns, different standards for data collection and reporting, different definitions of AMR, and limited data collection capacity in some countries [17, 24]. Given the importance of high-quality global surveillance data to track new resistance threats, it may be possible to develop an international body that provides funding and expertise for strengthening surveillance, while creating mandatory reporting and data sharing standards. Such a focused agreement could make use of Article 21 of WHO’s constitution, which allows for the development of new legally binding regulations without requiring ratification from its 194 member states through their regular national processes, because it falls within scope of the enumerated matters on which such regulations are allowed [16]. That being said, due to the multisectoral nature of the surveillance problem, a more focused treaty would still benefit from drawing upon the expertise of the WHO-FAO-OIE tripartite plus UNEP, instead of just one technical agency. This presents an alternative option: the United Nations General Assembly (UNGA) could adopt an AMR surveillance treaty using the joint enterprise method that delegates technical authority to the tripartite. This method would avoid regularly bringing contentious AMR issues to UNGA, increasing the potential to reach a consensus without risking ambition.

International law presents several opportunities to address the existing governance and market failures that have led to insufficient levels of antimicrobial innovation and to incentivize and facilitate the development of new antimicrobials and related technologies. The IHR, for example, could be revised to require national investments in research and development for new antimicrobials, alternative therapeutics, diagnostics, social interventions and infection prevention approaches that are proportional to national economic capacity and antimicrobial use. Existing legal mechanisms can also explore new and innovative funding models. In fact, some new and promising government and joint public–private partnerships have already arisen in response to the global challenge of restoring the pipeline for new antimicrobials [19]. But drug development has many stages and support is needed at all of them. In the absence of an overarching governance framework for funding AMR-related innovations, a disproportionate amount of money has been poured into basic scientific research in the form of early-stage push funding with fewer resources available for other types of needed research and at other stages of the innovation pipeline. This distribution, while a good start, can still lead to stagnation if discoveries in these early stages are not shepherded along the pipeline to later stages. Other later-stage push and pull funding mechanisms designed to bring drugs through clinical trial and into the marketplace are critically needed, but are lacking because of an absence of funding and governance [19]. Another viable alternative may be to consider fully public development models for drugs [20]. Better coordination on how innovation is funded is needed. A global pooled fund or institution governed by a single entity likely represents the best solution and can be housed as a joint enterprise between the WHO, FAO and OIE, and possibly managed by the Global Fund to Fight AIDS, Tuberculosis & Malaria.

Legal mechanisms can also be used to facilitate the development of new antimicrobials and their alternatives. At the very least, a dynamic list of all AMR-related research and development needs can be compiled and published by WHO, FAO, OIE and UNEP which could help to reduce inefficient duplications [21]. Such a mechanisms could not only develop product profiles, but also designate social outcomes for new technologies and approaches. Second, international law could address limitations in the way that new drugs are reviewed and approved around the world. Market authorization can be a long and costly process that diminishes the net potential value of new drugs, which further diminishes prospects for private investment in antimicrobial innovation [15]. Expedited review processes and internationally harmonized regulations under the TBT and International Conference on Harmonization could help. For example, if a new antimicrobial can be quickly approved in one country and then be subsequently and simply approved in other countries thereafter, it would significantly remove regulatory barriers that prevent new drugs from coming to market.