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Abstract

THIS PAPER HAS BEEN PUBLISHED IN THE JOURNAL ENVIRONMENTAL HEALTH. SEE FURTHER NEW ARTICLE PAGE: https://www.researchgate.net/publication/336145559_Managing_pollution_from_antibiotics_manufacturing_charting_actors_incentives_and_disincentives Background Emissions of high concentrations of antibiotics from manufacturing sites select for resistant bacteria and may contribute to the emergence of new forms of resistance in pathogens. Many scientists, industry, policy makers and other stakeholders recognize such pollution as an unnecessary and unacceptable risk to global public health. An attempt to assess and reduce such discharges, however, quickly meets with complex realities that need to be understood to identify effective ways to move forward. This paper charts relevant key actor-types, their stakes and interests, incentives that can motivate them to act to improve the situation, as well as counterincentives that may undermine such motivation. Methods The actor types and their respective interests have been identified using research literature, publicly available documents, websites, and the knowledge of the authors. Results Thirty-three different types of actor-types were identified, representing e.g. commercial actors, public agencies, states and international institutions. These are in complex ways connected by differing and partly similar interests that sometimes may conflict, sometimes pull in the same direction. Some actor types can act to create incentives and counterincentives for others in this area. Conclusions The analysis demonstrates and clarifies the challenges in addressing industrial emissions of antibiotics, notably the complexity of the relations between different types of actors, their international dependency and the need for transparency. The analysis however also suggests possible ways of initiating incentive-chains to eventually improve the prospects of motivating industry to reduce emissions. High resource consumer states, especially in multinational cooperation, hold a key position to initiate such chains.
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1
Title:
Managing pollution from antibiotics manufacturing: charting actors,
incentives and counterincentives
Authors:
Niels Nijsingha,b,c, Christian Munthea,b, D. G. Joakim Larssona,d; *
Affiliations:
a) Centre for Antibiotic Resistance Research (CARe) at University of Gothenburg, Gothenburg,
Sweden
b) Department of Philosophy, Linguistics & Theory of Science, University of Gothenburg,
Sweden
c) Institute of Ethics, History and Theory of Medicine, Ludwig Maximilian University, Munich,
Germany
d) Department of Infectious Diseases, Institute of Biomedicine, The Sahlgrenska Academy,
University of Gothenburg, Gothenburg, Sweden
* corresponding author
Email addresses:
niels.nijsingh@med.uni-muenchen.de; christian.munthe@gu.se; *joakim.larsson@fysiologi.gu.se
This is a preprint, the authorssubmitted manuscript before peer review to an article accepted for
publication in the scientific journal Environmental Health. A full open access version + appendix will be made
available when the final version is published. Citation should refer to that published version.
2
Abstract
Background
Emissions of high concentrations of antibiotics from manufacturing sites select for resistant
bacteria and may contribute to the emergence of new forms of resistance in pathogens.
Many scientists, industry, policy makers and other stakeholders recognize such pollution as
an unnecessary and unacceptable risk to global public health. An attempt to assess and
reduce such discharges, however, quickly meets with complex realities that need to be
understood to identify effective ways to move forward. This paper charts relevant key actor-
types, their stakes and interests, incentives that can motivate them to act to improve the
situation, as well as counterincentives that may undermine such motivation.
Methods
The actor types and their respective interests have been identified using research literature,
publicly available documents, websites, and the knowledge of the authors.
Results
Thirty-three different types of actor-types were identified, representing e.g. commercial
actors, public agencies, states and international institutions. These are in complex ways
connected by differing and partly similar interests that sometimes may conflict, sometimes
pull in the same direction. Some actor types can act to create incentives and
counterincentives for others in this area.
Conclusions
This is a preprint, the authorssubmitted manuscript before peer review to an article accepted for
publication in the scientific journal Environmental Health. A full open access version + appendix will be made
available when the final version is published. Citation should refer to that published version.
3
The analysis demonstrates and clarifies the challenges in addressing industrial emissions of
antibiotics, notably the complexity of the relations between different types of actors, their
international dependency and the need for transparency. The analysis however also
suggests possible ways of initiating incentive-chains to eventually improve the prospects of
motivating industry to reduce emissions. High resource consumer states, especially in
multinational cooperation, hold a key position to initiate such chains.
Keywords: Antimicrobial resistance; management, environmental pollution, policy
Background
Antibiotic resistance presents a serious and growing threat to global health. Effective
antibiotics constitute not only our most important tool to treat bacterial infections, but are
also critical for the effectiveness of many other areas of modern healthcare [1]. Use, misuse
and overuse of antibiotics, together with insufficient hygiene and infection control, are the
most important drivers of resistance on a global basis. As bacteria and bacterial genes often
move through the environment and across humans and animals [2,3,4], a ‘One Health’
perspective that takes all three of these domains into account is also necessary [5,6,7]. The
environment plays a role both in the transmission of resistant pathogens and as a source for
resistance factors that over time are transferred horizontally to pathogens. In both cases,
antibiotics emitted into the environment create a selection pressure likely to favour
resistant strains [8]. Antibiotic pollution occurs, partly, as a result of excretion from humans
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publication in the scientific journal Environmental Health. A full open access version + appendix will be made
available when the final version is published. Citation should refer to that published version.
4
and domestic animals. Although widespread, it is still uncertain to what extent the levels
found from such sources select for resistant bacteria [9]. In contrast, antibiotic pollution due
to wastewater emissions from manufacturing plants of antibiotics can be staggering, with
concentrations reaching into the mg/L range, constituting strong drivers of resistance [10]. It
is therefore not surprising that there is increasing recognition of the need for global
coordinated action to reduce industrial antibiotics emissions [4, 11, 12, 13, 14, 15].
This paper aims to contribute to the understanding of institutional aspects in this area that
are necessary for evidence-based and effective action. We present a map of actors that may
facilitate more effective pollution control and what incentives or counterincentives may
affect their ability to act. On this basis, we also address issues about sharing of key
responsibilities for initiating and sustaining effective measures to curb industrial antibiotics
pollution.
In the next section, we explain the theoretical background, the method we have used when
completing the map of actors and incentives, as well as the limitations of our analysis. In the
Results section, we use the taxonomy provided in the appendix and suggest that in
answering the question on who should act, we need to distinguish between ‘consumer’ and
‘producer’ countries. We then describe how actors in both antibiotic consumer and
producer countries can be motivated to effective action (incentives), as well as factors that
would hinder such motivation (counterincentives). In the Conclusions section, we
summarise the main findings, and expand our analysis to discuss the distribution of
responsibilities among the actor types. We conclude that high consumer states and certain
public institutions within these are in a key position to initiate effective change, especially
through multi-nationally coordinated actions.
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Methods
Any attempt to initiate effective actions to reduce industrial antibiotic pollution has to face
intricate realities when trying to decide what actions should be taken, and by whom. The
production, trade and consumption chain of pharmaceuticals is complex and involves many
actors with different interests. The challenge therefore needs to be approached from a
complex system perspective [16]. When considering the costs and benefits of various
interventions on specific levels and within specific sectors, we need to also consider how
different levels and sectors may interact to either favour or undermine better pollution
control. The interdependencies within and between systems and parts of systems of
different acting parties therefore need to be understood. This paper aims to take a first step
of contributing to such understanding by presenting a map of the relevant types of actors
with their respective interests, and describe possible incentives as well as existing
counterincentives (some of which already exist, while others may emerge due to policy
choices).
The are several proposals in the literature on how to address antibiotics pollution [3, 10, 11,
12, 13, 14, 15, 17, 18, 19, 20]. Despite providing important contributions, all of the above
focus on individual drivers and actors, leaving the systemic perspective largely unexplored.
A map of actors and their relations could therefore provide a clearer insight into the ways in
which these as well as future proposals may interact and function. The primary intention of
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publication in the scientific journal Environmental Health. A full open access version + appendix will be made
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the present study is not to argue for or against specific interventions, but to analyse how
different types of actions may either support and enhance, or come apart, conflict with or
even undermine each other. This will provide some general lines along which actions might
be designed and evaluated, and which actors should be thought of as responsible for
initiating and sustaining such developments.
Besides the peer-reviewed scientific literature, our material has included governmental and
corporate websites and policy documents. We thereby identified 33 types of actors, and
sorted these into a relational network that illustrates the actors’ main interests, and how
they may interact at and in between various levels (local, regional, national, international) in
light of these interests. On this basis, we then inventoried the ways in which these actors
may be incentivized to act, including regulatory, economic and political incentives. In doing
so, we make no particular assumptions about the underlying motivational patterns.
Specifically, we do not presuppose that actors always act fully ´rational´ or that they are only
driven by self-interest. Also, we largely put to one side driving forces that are common to
various actors, such as inherent tendencies of institutions to work in line with the
motivation of their individual employees [21].
The criterion for including actors was that doing so would add to the understanding of how
the different incentives and counterincentives may come apart or together in relation to the
aim of controlling industrial antibiotics pollution. Therefore, we have included a wide set of
actor types, but did not distinguish between single actors motivated by very similar types of
interests, as these are prone to be motivated by the same type of incentives. For instance,
we do not distinguish between different national political representatives or functions (as
these will likely be motivated by similar mechanisms), or between different public agencies
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guided by similar statutes and missions, or between different individual pharmaceutical
companies of the same type, and so on. We do, however, identify different types of political,
public, business or non-governmental bodies that seem to act out of relevantly different
types of interests.
The outcome of this analysis is a network of actors with attached interests and options to
act that may affect the options and/or stakes of at least one other actor. This result is an
important step to come closer to a comprehensive prescriptive social network analysis [22,
23]. Moreover, this step already facilitates informed hypotheses of promising policy
directions, and analysis of the proper sharing of responsibility to have such policy
development initiated. The entire network is mapped and described in more detail in an
appendix to this article. We use examples of specific national actors to serve as illustrative
“placeholders” for different national actor types. These have been taken from primarily two
contexts well known to us, India and Sweden. The analysis, however, is mutatis mutandis
applicable also to other legal and social contexts, although relevant differences may make
certain details different.
In the analysis we will henceforth refer to the actor types in the appendix by inserting # and
the number given to them there in parenthesis.
Results
Before considering possible options in some area in need of action, it is important to
consider what actors are able to effect suggestions. Who these actors are related to the
area of industrial antibiotics pollution is not straightforward. The most obviously involved
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type of actor is the pharmaceutical industry (#1-#5 & #7). However, as we show in the
appendix, once antibiotics (or API’s) are produced by subcontracted companies (#3), they
are often distributed across the globe by business networks (#1-#3, #7) which are complex
and often opaque, at least for the final customers and users (#20, #23, #24, #26, #28).
Through the mechanisms of global trade and linked regulation (#12) [20], the drugs
eventually find their way to what we label ‘consumer countries’ (see Appendix for more
detail). Depending on local regulative systems (#14-#19, #21, #22, #30, #31) and market
dynamics, different demands and prices are set in different places, and a combination of the
commercial actors interact with each other, as well as further ones, in chains of distribution,
retail and procurement. Although producer countries are also to some extent consumer
countries, and many consumer countries are also to some extent producer countries (by
hosting producers and distributors), we suggest that this distinction helps to understand the
various interests in play.
India and China are the largest hosts of subcontracted producer of APIs (#3), at least for
generic medicines. Europe and the USA on the other hand, host the largest research-based
companies (#1), while also representing large and economically strong markets for the
consumption of antibiotics. However, even though the majority of the final medicinal
products available on, for instance, the Swedish market are produced in Europe, the APIs
originate to a much larger extent from other parts of the world, often in countries with in
general ‘poor environmental standards´ [20]. To simplify, consumer states often ‘outsource’
the pharmaceutical pollution generated by their high consumption levels [10]. For this
reason, there will be differences between the typical interests of consumer states (#14),
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compared to producer states (#8), as the former have more indirect stakes in reducing
emissions, while they have a direct interest in reducing health care costs.
Any of the types of actors described in the appendix can conceivably affect the extent of
pollution by some type of action. At the same time, the actual choice regarding such actions
will be guided by a wide variety of interests, and take place in a very complex landscape of
other actors and interests. In what follows, we go on to examine in what way the actors may
contribute to a solution and how the levels interact, analysing what incentives and counter-
incentives may be created for producer actors, and for key actors in consuming countries,
using Sweden and India as examples.
Currently, there are limited legal or economic incentives for subcontracted producers (#3) to
act in order to improve the situation regarding industrial antibiotics pollution. Recent
initiatives by the pharmaceutical industry to address pollution indicate that the need to
change is recognised among some research-based companies (#1) [13, 24] but the costs
involved counterincentivize all producers from voluntary change. Obvious costs of
environmentally improved antibiotics production relate to more extensive efforts to avoid
contamination of wastewater in the first place or to install effective treatment (#6), which, if
the costs are reflected in prices, may lead to a smaller market share, or otherwise result in a
diminished profit margin: if the market shares remain the same while profit margin goes
down due to increased production costs, this means that the value of the market is
diminished, in turn affecting future flow of new investor capital. Also, the in-house
competence required to treat wastewater effectively is currently in many instances
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insufficient, necessitating further cost increases to build competence capacity in producer
countries. Likewise, information on the level of pollution at individual production plants and
how to assess these in a scientifically supported and reliable way is currently severely
lacking [10, 11, 12, 17, 25, 26, 27]. For this reason, setting up reliable systems to monitor
emission levels and types, and assessing when levels are acceptable and when they are not,
would probably be a major research and development investment, involving substantial
scientific, technical and staffing costs. The more that these costs have to be carried by
individual production companies (#1-#3), the more they will constitute a serious
counterincentive of both these companies and their owners (#5), as well as states and
individuals that benefit from their business (#8, #10), to go along with requests for better
control of industrial antibiotics pollution.
One way to provide incentives for desirable change of subcontracted producers (#3) is, then,
for other actors within the manufacturing country to take on (some of) the costs and the
logistical arrangements needed for an effective management of industrial antibiotics
pollution. For instance, the national government as well as regional governments (#8) may
sponsor research and development, financially support technological arrangements,
subsidize the cost of waste water treatment plants (#6) to assist in improved wastewater
management, and so on. In addition, governments may offer softer incentives by initiating
collaborative talks with industry, create benefit schemes for better performing companies,
etcetera. For example, the Chinese government aims to stimulate pharmaceutical
development by offering a competitive advantage by providing cheap electricity, land,
water, and waste disposal to companies that perform well in various respects, amongst
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11
which the tracking of medicine, transparency measures and environmental controls [28,
p.35]. Finally, the government can, of course, add incentives through regulatory
arrangements, laws, taxes, as well as charters for public agencies overseeing
pharmacological industry, environmental safety, etcetera. Here, the national environmental
agencies, such as the Central Pollution Control Board (CPCB) to take a specific Indian
example (#9) may conceivably play a larger role in surveillance and enforcement of
standards. However, to what extent the rather ambitious plans by Indian government to
curb pollution will be successful is yet to be demonstrated [15, 29]. Note that all of these
ideas shift the question to what incentives there are for these governmental actors to
actually take up this role of incentivizing producers. The financial, logistical and
infrastructural costs have to be paid somehow, at the end of the day by taxpayers who are
also donors and voters (#10). For a politician – regional or national – this provides a
counterincentive to taking the action that would incentivize all of the other actors to
pressure and assist the API producer.
Other actors that are in a position to incentivize subcontracted producers (#3) very directly
would be their customers (contractors), i.e. research-based (#1) and generic drug producers
(#2). If these actors start to require of their subcontracted producers to certify a good
antibiotics pollution management, it provides an immediate financial incentive for the latter
to do so. That would also create an immediate incentive for the state hosting the production
(#8) to provide resources and institutional frameworks to support such a development.
However, this raises the question how to incentivize research-based and generic producers
themselves to exert such pressure.
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One incentive for this chain of actors would be if there arises an internal national grass root
political pressure, and here the (national and international) media, science and international
organizations (#11, #13, #27, #29, #31- #33) may help to move things forward by creating
awareness of the potential risks associated with industrial antibiotics pollution. However,
such change usually moves slowly, and the question then arises what can be done to
incentivize action in the meantime. In addition, while awareness may certainly move
political opinion, it is far from certain that it would suffice to balance the mentioned
counterincentives.
One important counterincentive for action is the current general opacity of the production
and supply chain. This makes it a complicated task for governments and institutions (#8,
#14- #19, #30, #31) to create effective systems for control. For many companies, the
prevailing opacity also makes it quite risky to have the production chain be made more
transparent. Pharmaceutical companies may, of course, be motivated by reputation
concerns to avoid being perceived as antibiotics polluters. Rankings of public perception
[30] may have a significant impact on certain companies’ behaviour, but primarily those that
consider branding a critical issue of their business (#1). Again, this indicates that there is an
important role for scientists and media in revealing cases of (substantial) pollution.
Environmental agencies and NGO’s, both local and global, may play a similar role in
appealing to companies´ reputation concerns. NGO’s may not only apply (political) pressure,
but can also contribute by gathering data and documenting pollution and its effects. By way
of ‘naming and shaming’, such strategies can enable for example patients, hospitals,
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pharmacies and prescribing physicians (#20, #23, #24, #26, #28) to exercise their power to
apply pressure – we will further expand on how they may do this below.
But reputation concerns are a factor mainly for research-based companies (#1), as these
have a brand to protect in the eyes of public perception. In contrast, generic producers (#2)
and subcontracted producers (#3) do not, or at least not to the same extent, have a need to
protect reputation in order to stay in business. Reputation may, however, indirectly concern
many large investors in pharmaceutical companies (#5). Financial institutions, such as banks,
insurance companies and pension funds, have been shown to be sensitive to pressure from
consumers and advocacy groups (albeit slowly and not always effectively, see 31, 32).
However, since it is sufficient for protecting the reputation of a market brand that a
company seems to act in a responsible and sustainable manner, there is a lack of incentive
to push for a more transparent system. Companies can be reluctant to share information to
make the production chain more transparent for the very reason of protecting their
reputation. These counterincentives will also likely affect investors. Paradoxically, therefore,
reputation concerns may provide counterincentives to effective antibiotics pollution action.
While pharmaceutical companies show an increased willingness to take antibiotics pollution
seriously, (13) given the current lack of transparency of how industrial antibiotic emissions
link to specific research-based producers, very few are willing to disclose information that
would make the situation less opaque, such as identifying who their subcontractors are and
what levels of antibiotics they emit to the environment (14).
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However, had the production and supply chains been reasonably transparent, the incentive
coming out of a research-based company’s concern for reputation would seem to have
pulled in the opposite direction. Once the world can see whether this company is tainted by
a high polluting chain (and there exists a general awareness of the industrial antibiotics
pollution problem that means companies would be potentially hurt by such a perception), it
starts to make good sense for research-based producers (#1) and their owners (#5) to avoid
being associated with such chains and promote chains with a higher level of sustainability.
Based on this, research-based companies acquire reasons to pressure subcontracted
producers (#3), and thereby initiate a chain of incentives for constructive change supported
by producer countries (#8) in line with what was envisioned above. However, generic
producers (#2), as observed, will not be incentivized to the same extent (as their brand is
not as critical to protect), which means that insofar as the sales for generics are not that
sensitive to improvement in transparency, these producers will be less incentivized to
pressure subcontracted producers. Unfortunately, this factor will then add to the
counterincentives of research-based companies to work for increased transparency of the
production chain, since this would put them at a relative business disadvantage when
compared to the generic producers. While generic producers would be able to by APIs more
cheaply from subcontractors, research-based companies would have to carry parts of the
costs for a more sustainable API production.
It should be clear at this point that understanding how markets function is important for the
analysis of how to incentivize producers, and relevant actors in producer countries, towards
more sustainable practices with regard to industrial antibiotic pollution. In a market, the
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relative advantages and disadvantages of stakeholders are in the forefront of how business
actors (and those with interests closely linked to these) assess the attractiveness of a more
sustainable strategy. Unless there is an added benefit, companies are understandably
reluctant to exert themselves overly when the competition is unlikely to incur similar costs.
This strategic consideration illustrates the importance of finding ways to incentivize all types
of producers (#1-#3) equally, in turn pointing to the importance of creating internationally
harmonized policies and to an important role for internationally coordinating institutional
actors (#12, #13, #30, #31) in order to have effective incentive structures in place. On the
other hand, there is a danger in strategies that rely on all relevant actors being on board:
aiming for global consensus across all actor types may well lead to passivity.
Given the multinational and complex nature both of the drug market and international
politics and trade, therefore, consumer countries seem to be in a key position to support a
functional development of the international regulative landscape. This particularly regards
affluent consumer states, such as Sweden (and, in association with other states similarly
placed, the EU [33]) and the USA. This moves our search light from the producers and
producer countries to those that dominate consumption.
Although there is good reason to look at consumer countries in developing a response to
industrial antibiotic pollution, there are significant obstacles in the way. A counterincentive
that stands out is an unwillingness to accept increased healthcare costs, as all of the
incentives for industry mentioned can be expected to be reflected in pharmaceutical prices.
Systems for generic substitution of drugs that we will discuss below are a particularly
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institutionalized example of this counterincentive. However, there are various ways to
counter such obstacles. Below, we highlight licensing, reimbursement and procurement
mechanisms in this respect. It should be noted that media and scientific researchers (#32,
#33) play a role in increasing awareness among institutional and political actors in high
consumer states such as Sweden (#14 - #25), and international political collaborative
organisations, such as the EU and the UN (#12, #13, #30, #31), helps to promote this sort of
development. We will start by mapping out potentially effective actions that could create
incentives for positive change, and after this list counterincentives to having the listed
actors take these actions.
One powerful tool to motivate pharmaceutical companies is through licensing requirements
and the routines of institutions in charge of implementing these (#15, #31). In the EU,
licensing of medicinal products is to a large extent harmonized, which offers promising
opportunities. When applying for a European marketing license, pharmaceutical companies
are required to submit an environmental risk assessment (ERA) to the EMA or a national
competent authority within an EU country [34]. The ERA covers a broad set of
environmental assessments with a clear possibility to incorporate considerations relating to
antibiotic resistance. However, to date, such risks are not covered within this regulation.
Also, only pollution associated with usage (not production) is covered within the ERA. The
need for amending the ERA to bridge these two gaps have been pointed out earlier [17]. At
the same time, in practice, there is no penalty for non-compliance and products are not
withheld from the European market based on non-compliance with the ERA [17]. In
contrast, the risk-management plan, which assesses amongst other things the safety of the
medicine for the patient, is used to determine eligibility for a license on the European
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market, and similar mechanisms may be used by national agencies. Addition of an amended
ERA (to cover industrial pollution as well as environmental dimensions of antibiotic
resistance) as a required ingredient in the risk-management plan (and equivalent national
requirements), would therefore produce a substantial incentive for companies to mind
about the sustainability of their production chain. In addition, it would be a basis for
licensing agencies to require a transparency of this chain for the purpose of assessing the
environmental footprint of a drug, specifically with regard to antibiotic pollution. Such a
requirement may be applied to both research-based and generic producers, and may be
extended also to parallel import distributors in regulations for permission to trade in drugs,
all in order to create equal conditions on the market. At the same time, the nature and
function of the risk assessment involved in the licensing of drugs means that considerations
relating to pollution would have to be weighed against other considerations, such as need,
efficacy, safety, and the availability of alternative treatment [17]. This means not only an
uncertain upshot, but also possible risks of ethical controversy and political backlash [35].
More robust incentives of this kind could be created through the fact that pharmaceutical
companies active on the European market are bound by the EMA Good Manufacturing
Practices [36]. These are not relative in the way that single risk factors in the risk
management plan are. Although currently environmental considerations are not considered
in the GMP, they could be devised to include discharge limits, requirements of disclosure
with regard to production chains, and other relevant demands to secure a minimum level of
sustainable production practices. As the possibilities to follow up on requirements and
effectively control compliance are currently limited [10,17], such control would require
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18
stronger international collaboration, something on which the European Commission hints in
the ‘EU action plan’ [33]. Unfortunately, however, the action plan remains vague about the
specifics of such support, and focuses mostly on the value of more knowledge, without
committing to robust incentives in the pharmaceutical market, let alone licensing practices.
To get the ball rolling towards incentivizing research-based and generic producers to
become more transparent with regard to production chains, and to require of
subcontracted API-producers to monitor and disclose emissions, as well as to mitigate these
emissions to acceptable levels, explicit regulatory requirements seem to be necessary. This
probably requires national and international political action by high consumer states (#12-
#14, #30), but once that ball is set in motion, incentives for institutional actors to assist and
press industry actors and producer country institutions will likely follow.
A complementary action is to require that information detailing the production sites of
antibiotic products are made publicly available, as this would open up the environmental
performance of the production chains for public scrutiny. Such information could be given
on websites, (for example the producer´s own or that of the European Medicines Agency
(#31)) alternatively labelling on containers (which is highly regulated) or pharmacy shelves
[37]. The information could include the exact location of where the constituting API’s are
produced and formulated (a mention of only the country or region of origin would have very
limited value [20]), the companies involved in these stages of the drug production, as well as
information on applied discharge limits (voluntary or enforced) and the documented level
emission control. However, this type of strategy becomes effective only when it feeds into a
consistent customer demand mechanism that will create incentives for companies to offer
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publication in the scientific journal Environmental Health. A full open access version + appendix will be made
available when the final version is published. Citation should refer to that published version.
19
products produced under demonstrably sustainable conditions. When the distribution of
drugs in general, and antibiotics in particular, is controlled directly or indirectly (for example
through prescription guidelines) by national or regional institutional actors within consumer
countries, this may be the case to the extent that these actors make explicit requirements
with regard to production chain disclosure and guaranteed emission levels. In large parts of
the world today however, the market in antibiotics is not consistently institutionalized,
there are no, or very weak, prescription requirements, and most health care and pharmacy
is operated through small-scale private actors [38]. In these health systems increased public
awareness created through actions by the media, NGO’, patient, professional and academic
actors (#27, #29, #32, #33) may help to produce some effect. However, in both cases the
effects of such incentives are uncertain. Once again, this moves the search light to consumer
countries, and the way their internal actors chose to position themselves. For those
countries that lack institutional control over drug distribution and consumption, the first
step would then be to create the needed frameworks, admittedly a formidable political task
for these consumer states (#14). In the following, we limit ourselves to high consumer
countries that do have such frameworks, taking our specific examples from Sweden.
The Swedish government (#14) has so far addressed the issue of the environmental
dimensions of pharmaceuticals with greater force than the EU (#30), although there is some
recent progress in the European context as well [39]. For example, on instruction from the
government, the licensing authority Läkemedelsverket, LV (#15), has explicitly addressed the
issue of pharmaceutical pollution [40]. However, the resulting incentives are still limited,
due to similar factors as already mentioned in the case of EMA. Although LV has made
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publication in the scientific journal Environmental Health. A full open access version + appendix will be made
available when the final version is published. Citation should refer to that published version.
20
constructive proposals to incorporate more stringent demands in ERA and Good
Manufacturing Practices as formulated by the EMA, they have little, if any, room to pursue a
course independent from the European context in this respect. A revised GMP framework
would put equal demands on all antibiotics sold on the European market, but progress in
this direction has been slow.
Additionally, a Swedish government white paper has suggested that a system of premiums
related to industrial pharmaceutical pollution behaviour might be a way forward: “An
alternative way of creating incentives for environmental adaptation within the framework of
the pharmaceutical reimbursement system is through voluntary environmental classification
and an environmental premium.” [41, p. 33] It is clear that such a system, if the premium is
sufficiently high, may do much to address the issue of stimulating greater transparency and
offer a strong concrete business incentive for industry to curb emissions. An immediate
question that arises, however, is how such a system should be designed, who would end up
paying the cost, and how motivated will key political actors be to accept them? In addition,
a well-functioning premium system involves calculating the environmental costs,
establishing criteria for conformity etcetera [41, p. 34]. The LV also makes decisions on the
interchangeability of drugs within the Swedish ‘generic substitution system’ [42]. The
Swedish system dictates that if two drugs are interchangeable, the cheaper of the two will
be given preference in the subsidizing and healthcare procurement system. The criteria for
interchangeability relate solely to clinical risks and benefits, meaning that generic producers
with lower production costs are often favoured against research-based producers and there
is no special consideration of environmental considerations.
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21
However, given these decisions on interchangeability, the public subsidy authority
Tandvårds- och läkemedelsförmånsverket (TLV, #16) may act within its authority on the
allocation of the public subsidy of drugs. When comparing products which are considered
interchangeable, the TLV may include pollution criteria, such as requirements related to
industrial pollution [41]. This would incentivize not only research-based producers, but also
generic producers. Yet, given the current assignment by the government instruction, the
TLV appears to have very little room to make substantial environmental demands.
Furthermore, in the EU (and Sweden), this particular incentive will be limited, as generic
substitution only comes into play after a patent has expired [41, 43]. On the other hand, the
overwhelming amount of antibiotics (in terms of doses, not necessarily money) are for
antibiotics whose patents are indeed expired.
All of these governmental actors may thus act to include in their decision rationales
considerations related to industrial pharmaceutical pollution, both as an internalized
external cost that counts as a reason against buying or prioritizing a drug, and as a benefit
when companies demonstrably act to make pollution management more sustainable.
Already within current charters, all of these actors have the opportunity to weigh in
environmental considerations. However, as documentation is lacking on the basis of which
such an assessment could be made, in order to incorporate antibiotics pollution as a
criterion, more information regarding the actual level of pollution management would be
required (11, 41).
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22
In theory, pharmacies could also be an important actor with regard to generic substitution,
having patients select the environmentally more preferable among therapeutically
equivalent drugs. In Sweden, however, they would be constrained by the generic
substitution system, and the decisions by LV and TLV for prescription drugs (which all
antibiotics are). Unless these latter actors weigh environmental factors into their decisions,
this remains impossible for pharmacies. In states where pharmacies have a license to act
more autonomously, this role may remain open. Another way in which pharmacies may
contribute to the right incentives, is by labelling practices. For example, there is in Sweden a
voluntary labelling initiative by the private pharmacy chain Apoteket Hjärtat, which involves
labelling on the shelf. This labelling is, however, limited to procedural company
characteristics, whether they follow a certain reporting system and are part of the
“pharmaceutical supply chain initiative” [37, 44]. Also, such labelling practises by the
pharmacies are not applicable to prescription drugs.
Separate from the pharmacies (and thus the issue of interchangeability), incentives may be
offered in the context of public procurement [45, 46]. As described in the appendix, Swedish
public hospitals and primary care clinics are usually either owned or subcontracted by the
county councils, who buy and negotiate antibiotics. The amount is relatively minor when
compared to the total amount of the antibiotics that are used in Sweden, but still
substantial (#20, #21). In addition, county councils subcontract to privately owned hospitals
and clinics. County councils are therefore in a unique position to lay down environmental
demands, and therefore may contribute an important piece of the puzzle in providing
effective incentives to pharmaceutical companies. Nationally, the public procurement
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23
agency, Upphandlingsmyndigheten (#19), in turn, can help guide county councils in a
supporting advisory role. In addition, the inter-regional body for national price negotiation
and priority setting of new treatments within the organization of counties and
municipalities, especially NT-rådet (#22) [47] can help counties act jointly and effectively by
taking environmental considerations into account when assessing the overall value of a
drug, and make environmental demands in these negotiations. Additionally, county
government and other regional actors (#20, #21), which have the final mandate to decide
what treatments are “on the menu” to be procured by public hospitals and primary care,
may take similar steps with a similar impact.
Another possible pathway to create incentives based on LV and EMA decisions on drug
licenses is clinical guidelines. We have already mentioned regional committees issuing
recommendations on what drugs to use for given indications (#21). At the same time the
national agency, the Socialstyrelsen (SoS) (#17), has a powerful and coordinating position
role in issuing national treatment guidelines. Given the strategic threat to the quality of
healthcare generally it may not be unreasonable to have such guidelines allow room for
environmental health considerations as part of the rationale. The government (#14) may
give SoS such a charter, and direct it to collaborate with the Public Health Agency of Sweden
(FHM) (#18) in this endeavour.
All ideas of changing the system for drug substitution conflict with the underlying policy
rationale of this system. The point of such systems is to reduce the public cost for
pharmaceuticals by exploiting the competition between research-based and generic
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24
producers. Generic drugs ruled to be interchangeable are given fast access to the market
and public subsidy, thereby making cheaper alternatives quickly procurable for healthcare.
Measures as the ones mentioned above mean that generic manufacturers (which are not as
sensitive to other pressures to control environmental emissions) will probably lose
competitive advantage. At the same time, there is a strong political interest in reducing
healthcare costs, linking to an interest across large segments of the public in avoiding tax
increases. This creates a counterincentive against implementing reform of the drug
substitution system that could incentivize producers to better control industrial antibiotics
pollution. This counterincentive is an unusually salient and specific example of how widely
embraced political aims to reduce pharmaceutical cost in publicly funded health systems
undermines motivation to take action that could incentivize industry and producer countries
to control industrial antibiotics pollution. Simply, put, whatever actions are taken, these will
probably be reflected in drug pricing, and thus run contrary to currently prevailing economic
health policy aims on many high consumer states.
Specifically, incentives concerning the interchangeability or subsidy of drugs meet with the
underlying logic of the generic substitution system. The system aims to reduce the public
cost for pharmaceuticals by exploiting the competition between generic and research-based
producers on the market. Generic drugs ruled to be interchangeable are given fast access to
the market, while public procurement and the reimbursement system are strongly directed
towards choosing the cheaper alternative. Measures as the ones mentioned above have to
be directed against both these types of producers to be meaningful, meaning that generic
manufacturers that currently achieve lower prices, which partly may be due to less spending
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publication in the scientific journal Environmental Health. A full open access version + appendix will be made
available when the final version is published. Citation should refer to that published version.
25
on controlling environmental emissions, will probably lose competitive advantage. At the
same time, there is a strong political interest in reducing healthcare costs, linking to an
interest across large segments of the public in avoiding tax increases, making it more
rational to resist actions undermining such interests. In the long run, of course, this
counterincentive weighs quite lightly in the face of the antibiotic resistance threat. Also, the
economic interest that drives this type of counterincentive clearly weighs quite lightly in the
face of the antibiotic resistance threat. This holds even if we grant the interest of a state to
control healthcare costs, as this interest assumes the primary value of having an effective
health system, which is in turn threatened by antibiotic resistance. However, longer time
horizons are seldom very decisive in politics, unless there is a stark public awareness of very
serious threats. Here, as before, media (#32), NGO’s (#11) and academic and professional
actors (#26, #33) may act to shape a public atmosphere weakening this counterincentive.
Especially academics and professionals are in a key position to provide the understanding
and information in order to prompt such a development, since, although typically their
audience is limited, scientists and professionals play a crucial role in making public the
relevant facts.
A recurring counterincentive for many of the actions that could be taken by national
institutional actors has its root in well-known collective action problems related to global
problems [48, 49]. There are Swedish county councils (#20) that have requested from
pharmaceutical companies that emissions are monitored during manufacturing, but on their
own their negotiating power vis-à-vis multinational corporations is weak. Actors within the
counties, such as single hospitals (#20), the Läkemedelskommitté (#21), or pharmacies (#24)
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publication in the scientific journal Environmental Health. A full open access version + appendix will be made
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26
have even less power in this respect. For this reason, nationally coordinating institutions like
LV (#15), TLV (#16) and NT-rådet (#22) have a stronger incentive to act in this respect, but
we have also seen that their mandate is limited. Therefore, the counties here primarily face
an incentive to start acting even more in coordination, in order to create an incentive for
each to use the procurement and priority setting incentive. However, even if this mandate
would be expanded by the state (#14) to facilitate also more effective and such well-
coordinated national action, the state level actors face a situation where the difference that
they can make on their own is limited. Sweden has a relatively small mass in terms of drug
industry revenue (0.9% of the global market value of pharmaceuticals), suggesting that any
effective intervention of the types mentioned is likely to be rather costly. If the EU (#30), or
better yet the global community, were to formulate joint demands, this would result in a
much more powerful position to incentivize large international industrial conglomerates.
However, as we have already seen, in the European context, let alone the global one, the
legal power of the relevant institutions is relatively weak: the EMA (#31), for example, has
as its primary purpose streamlining the national policies decided by single states, not
initiating effective joint action. This is a counterincentive against EMA acting in the direction
sketched earlier to create incentives for pharmacological companies to mind more about
environmental factors. And as we move into global institutions (#12, #13), while potential
bargain power becomes very much stronger when these do succeed to act forcefully, the
political base to further an independent agenda restrict the policy options of sovereign
states proportionally weakens. Therefore, at the end of the day, this counterincentive can
be mitigated or removed only to the extent that a sufficient number of single high consumer
states are motivated to coordinate effective action to incentivize producer states and
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publication in the scientific journal Environmental Health. A full open access version + appendix will be made
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27
industry. Once again, academic and professional actors, NGO’s and the media have a key
role for incentivizing such motivation.
Another underlying counterincentive to effective institutional action (on any level) is the
current lack of effective surveillance systems and systematic emission data on industrial
antibiotic pollution [10]. This is the case because effective action requires specific
information to act upon, but also because such information affects prioritization in order to
direct incentives to the appropriate targets. This holds on the national (Swedish or other
single consumer states) as well as the multinational (EU and, ultimately, UN agencies) level.
Therefore, a first step needs to be to incentivize better industry transparency with regard to
production chains, as well as demonstrable actions to monitor and control emissions at the
source [18, 20] Lack of transparency and documented action in this respect creates an
environmental health uncertainty that can be viewed as an external cost for society that
needs to be internalized in different ways by different actors, thereby making a drug less
attractive for license, clinical recommendation, subsidy, procurement and prioritizing. The
higher this cost is estimated by a societal institutional actor, the more forceful the incentive
for companies to act in order to favour their own products. Once a system of reasonable
transparency regarding production chains and quality assured monitoring of emission levels
is in place, the counterincentive for societal actors is gone and the search light can move to
actual emissions, so that companies can be rewarded for assuring effective curbing of
antibiotics pollution through measures at own plants, or pressures on subcontracted
partners.
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28
Conclusions
In this paper we have mapped important incentives and counterincentives with regard to
possible ways in which actors that are directly or indirectly involved in the issue of industrial
antibiotic pollution can be motivated to effective action (incentives), as well as to obstacles
that would hinder such action (counterincentives). Taking account of all of the actor types,
and their possible incentives and counterincentives to act effectively in this area, described
in the Results section, we may plot typical chains of actions and resulting incentives
(including overcoming noted counterincentives), and use this as a starting point for actors to
decide how to design policies and specific measures and where, more exactly, to direct
these. An example of this is found in Figure 1.
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29
Figure 1 to be inserted here
Figure 1: Examples of chains of actions of different actor types to incentivize action of other
actors to improve the management of environmental industrial antibiotics pollution
As noted, some possible actions may create tensions between different normative
considerations. For instance, incentivizing through reform of drug licensing and clinical
guidelines may create provocative tensions between long-term environmental health
considerations related to industrial antibiotics pollution and ordinary short-term clinical
ethical considerations regarding benefit and safety for patients in care. As mentioned,
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30
political normative conflicts between short-term aims to reduce healthcare cost may also
conflict with many incentives that can be created by consumer state actors. We are not here
arguing for any particular resolution to such dilemmas, neither have we to any specific
conclusion on what from a normative perspective is the right course of action for the
various actors involved (although we have pointed out some normative considerations). We
only note that all of these actors, based in the main interests driving their choices, share a
long-term interest in effective management of antibiotic resistance. For this reason, given
the complex situation described, even business actors may have good reasons to welcome
state action, even if it involves regulatory measures restricting business freedom. It is likely,
however, that regulatory solutions alone will not suffice and that we should also look at
economic incentives and aid for capacity building in producer countries and the role of
information when we look for possible solutions to create better transparency and, once the
information facilitated by that is available, effectively aligned systems in consumer countries
to stimulate sustainable production models. Thus, it is difficult not to conclude that the
main responsibility for initiating a positive development in this area rests with high
consumer countries, especially ones of larger importance for commercial companies, and
preferably in collaborative concert. However, exactly how such a mix of regulation, aid and
“carrots and sticks” should be designed in detail remains to be worked out. Any plausible
approach to effectively reduce industrial antibiotics emissions will likely involve various
‘carrots and sticks’ in the form of economic or political incentives [3, 10].
The collective action challenge presented by industrial antibiotic pollution is an outcome of
how effective incentives to combat industrial antibiotics emissions rely on action on
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available when the final version is published. Citation should refer to that published version.
31
different levels and how these levels interact in sometimes rather complex ways. This
interconnectedness, and the complexity it involves, is itself a feature of the problem at hand
that needs to be taken into account when considering solutions. We have shown how as
long as producer countries remain insufficiently effective in enforcing strict regulation,
incentives for actions to curb industrial antibiotics pollution in these countries (especially
those hosting subcontracted API manufacturers) are unlikely to arise without considerable
support action by consumer countries and the international community. We have also
demonstrated that the creation of systems to make production chains transparent, and
emission levels controllable, plays a crucial role in addressing the problem of antibiotics
pollution. Without such systems, very little actions of any other kind seem likely to
motivate, no matter what actor perspective we take.
The combination of these three challenges (complexity, international dependency and need
for better transparency) are common to various ethical problems of a systemic and global
nature: think of diverse global topics, such as climate change, human rights issues in the
production of globally traded consumer goods, animal welfare in meat production and the
use of pesticides in agriculture. For each of these areas, a relatively large number of
different actors constitutes a complex chain or network in which each of them is dependent
on what the others do. Transparency and controllability are crucial to the success of any
attempt to address such situation policy issues, and this for two reasons. First, transparency
and controllability provide quality assured insight into the problem and how possible
solutions proceed. Second, the notion of global cooperation requires that actors have
knowledge of what the others are doing and how joint action pays off. This is not necessarily
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32
an indication of mistrust, but a condition for creating meaningful options for action that can
be viewed as legitimate from the different perspectives of different types of actors and
different states. In order to address complex issues such as industrial antibiotic pollution, we
need to consider in what ways actors can create space for other actors to acquire
information that is important for them to act effectively downstream. Viewed in this way,
pursuing the construction of systems and standards for transparency and control will likely
mean very different things on different levels. The analysis in this paper suggests that high
resource consumer states, especially in multinational collaboration, hold a key position to
have the chain of incentives commence by making customer requirements incentivizing
industry to create the required systems and standards.
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42
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
Not applicable.
Availability of data and material
Data sharing is not applicable to this article as no datasets were generated or analysed
during the current study.
Competing interests
The authors declare that they have no competing interests
Funding
This research was supported by the Swedish Research Council (VR) grant no 2018-05771
and the UGOT Challenges Initiative at the University of Gothenburg.
Authors' contributions
DGJL conceived the idea, and developed the general approach of this paper together with
CM. NN analyzed the sources and drafted the first version – after that all authors
contributed equally. All authors read and approved the final manuscript.
Acknowledgements
NN would like to thank Henrik Friberg-Fernros for the opportunity to present a draft version
of this paper at the Practical Philosophy and Political theory workshop, at the Gothenburg
University, on January 15 2019, as well as for his valuable comments on that draft.
ResearchGate has not been able to resolve any citations for this publication.
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