- Contents lists available at sciencedirect.com
Journal homepage: www.elsevier.com/locate/jvalPolicy PerspectiveAntimicrobial Resistance: Is Health Technology Assessment Part of the
Solution or Part of the Problem?
Abigail R. Colson, PhD, Alec Morton, PhD, Christine Årdal, PhD, Kalipso Chalkidou, MD, PhD, Sally C. Davies, GCB, DBE,
Louis P. Garrison, PhD, Mark Jit, PhD, Ramanan Laxminarayan, PhD, Itamar Megiddo, PhD, Chantal Morel, PhD,
Justice Nonvignon, PhD, Kevin Outterson, JD, John H. Rex, MD, Abdur Razzaque Sarker, PhD, Mark Sculpher, PhD,
Beth Woods, MSc, Yue Xiao, PhD1098-30
open acA B S T R A C T
Antimicrobial resistance is a serious challenge to the success and sustainability of our healthcare systems. There has been
increasing policy attention given to antimicrobial resistance in the last few years, and increased amounts of funding have
been channeled into funding for research and development of antimicrobial agents. Nevertheless, manufacturers doubt
whether there will be a market for new antimicrobial technologies sufficient to enable them to recoup their investment.
Health technology assessment (HTA) has a critical role in creating confidence that if valuable technologies can be developed
they will be reimbursed at a level that captures their true value. We identify 3 deficiencies of current HTA processes for
appraising antimicrobial agents: a methods-centric approach rather than problem-centric approach for dealing with new
challenges, a lack of tools for thinking about changing patterns of infection, and the absence of an approach to epidemio-
logical risks. We argue that, to play their role more effectively, HTA agencies need to broaden their methodological tool kit,
design and communicate their analysis to a wider set of users, and incorporate long-term policy goals, such as containing
resistance, as part of their evaluation criteria alongside immediate health gains.
Keywords: antibiotic agents, antimicrobial resistance, economic evaluation, health technology assessment.
VALUE HEALTH. 2021; 24(12):1828–1834Introduction: The Growing Threat of
Antimicrobial Resistance
The spread of antimicrobial resistance (AMR) is a key challenge
for healthcare systems. Modern medicine depends on
antimicrobial agents to treat disease and ensure that surgery,
chemotherapy, and a range of other treatments can proceed
without the risk of life-threatening infection.1 Nevertheless, using
antimicrobial agents promotes resistance, opening up an
ecological niche in which resistant pathogens can thrive. Almost
80 years of history of antibiotic use shows that within a few years
of introducing an antibiotic, resistant pathogens emerge. In recent
years, resistance to both colistin, the last line of treatment for
many bacterial infections,2,3 and artemisinin, the core element of
effective combination therapy for malaria,4 has been detected.5-7
The World Health Organization (WHO) estimates that, in 2016,
a total of 490 000 people worldwide developed multidrug-
resistant tuberculosis.8 The European Centre for Disease
Prevention and Control estimates that drug-resistant infections
killed 33000 people in Europe in 2015,9 and in 2019 the US
Centers for Disease Control and Prevention estimate they kill
35000 patients in the United States annually.10 Forecasts suggest15 - see front matter Copyright ª 2021, ISPOR–The Professional Society for
cess article under the CC BY-NC-ND license (http://creativecommons.org/licthat, without action, drug-resistant infections could cause millions
of deaths annually and significantly reduce global gross domestic
product by 2050.11,12 AMR is a public health emergency, damaging
human (and nonhuman) health worldwide. It is likely to have
considerably greater impact on health and well-being in the
future, with the greatest health and economic impact occurring in
low-income settings.11 This threat may worsen in the coronavirus
disease 2019 era, because of the use of antibiotic agents to control
infections in hospitalized patients with COVID-19.
Several vital steps have been suggested to combat AMR. These
include controlling the use of antibiotic agents in farming and
reducing levels of antibiotic agents in wastewater. In many
countries with poor access to healthcare, widespread
inappropriate consumption of antimicrobial agents coexists with a
lack of access for patients in genuine need.13 Hospitals and other
healthcare facilities need to improve their antimicrobial
stewardship and infection prevention and control practices, and
patients need to moderate their expectations about the availability
of antimicrobial agents. Tackling these issues can reduce
resistance rates and preserve antimicrobial efficacy, but the
struggle against AMR also requires new technologies, such as
innovative antimicrobial agents and improved diagnostics that canHealth Economics and Outcomes Research. Published by Elsevier Inc. This is an
enses/by-nc-nd/4.0/).
POLICY PERSPECTIVE 1829help target antimicrobial agents, ensuring they are only used
when necessary. New and existing vaccines can also help, through
tackling the spread of microbial diseases generally or resistant
strains specifically.14
Despite the need for new technologies, the WHO has said the
clinical antibacterial pipeline is not sufficient.15-17 Large
pharmaceutical companies such as Sanofi, Novartis, and
AstraZeneca have stopped their antimicrobial development
programs.18 High development costs, the availability of cheap
alternatives, and the small potential market for new antimicrobial
agents (in part because of the necessity of ensuring appropriate
stewardship of novel therapies) reduce the economic incentives
for research and development (R&D) of new antimicrobial agents,
creating a need for innovative policy and thinking to support R&D
efforts.Why Does This Matter for Health Technology
Assessment?
AMR has ascended the international policy agenda (Table 1),
and this political attention has been matched with increased
funding to support R&D of antibiotic agents: the international
nonprofit funding vehicle CARB-X is supporting more than 80 new
antibiotic R&D projects with funding up to $500 million over 2016
to 202129,30; the REPAIR Impact Fund will spend $165 million over
the next 5 years as an investor in antibiotic R&D31; and Global
Antibiotic Research and Development Partnership, a nonprofit
cofounded by WHO, and the Drugs for Neglected Diseases
Initiative focusing on health needs in low- and mid-income
countries (LMICs) have cofunded phase III trials for a new drug
for gonorrhea.32,33
These initiatives are an important step, but new technologies,
however clinically promising, will not be available on the market
unless investors have a clear path to secure an adequate return.
Currently, potential investors doubt whether these technologies
represent a viable business proposition. The recent failure of
Achaogen, a biopharmaceutical company that brought
plazomicin—a new antibiotic capable of treating multidrug-
resistant infections—to market in 2018 but filed for bankruptcy
in April 2019,34 demonstrates the validity of these concerns. The
application for market authorization in Europe for plazomicin was
withdrawn in June 2020,35 and omadacycline had a similar fate
the previous October,36,37 with both withdrawals substantially
driven by economic infeasibility.
One way to match demand for a new technology to clinical
need is through the use of health technology assessment (HTA),
which estimates the cost-effectiveness of a new medical
technology and suggests to payers whether or not the product
should be reimbursed. HTA bodies in some countries go a step
further and use cost-effectiveness analysis to also establish the
price to be paid, which is called value-based pricing. HTA—which
is not limited to formal cost-effectiveness analysis—informally or
indirectly supports decisions about eligibility and/or price
negotiations in other countries and is increasingly being
recognized as an important tool for priority setting in LMICs.38,39
Many smaller countries follow the lead of larger countries in
matters of access, pricing, and reimbursement through external
reference pricing. Thus, HTA plays a critical role, through both HTA
agencies’ recommendations about technologies and the
perception of how they arrive at their recommendations, which
has a direct impact on investments and which technologies are
profitable.
Given this central role of HTA agencies, the way in which they
assess whether new technologies offer value for money is veryimportant. An inappropriate assessment of value could mean that
manufacturers are unable to earn a return on their investments,
signaling that a given product should not be brought to market.
Here, we argue that in the case of antibiotic agents agencies are
not routinely using appropriate evaluation methods, and they are
approaching their assessment from a perspective that blinds them
to many of the elements of value provided by new antimicrobial
agents.40Clinical and Public Health Value of Antimicrobial
Agents
Critical to understanding the value of new antimicrobial agents
is the notion of disease transmission. When a patient hosts a
pathogen that has evolved to be resistant to standard treatment,
this patient may transmit this pathogen to others, potentially
leading to a costly and damaging outbreak of resistant infections.
If an innovative technology exists to treat a patient with the
resistant pathogen, the spread of resistance can be reduced. In this
sense, antibiotic agents are like a fire extinguisher that, at a
modest cost, prevents the whole house from burning down.41
Most therapeutic medical technologies only benefit the
individual patient, whereas antimicrobial agents (as well as
diagnostics and vaccines) indirectly benefit the wider society.
Nevertheless, unlike diagnostics and vaccines, if treating someone
reduces the demand for treatment from other patients, the
antimicrobial manufacturer makes a lower return if they are paid
per dose. Ignoring this “positive economic externality” is one
market failure at the heart of the mispricing of innovative
antimicrobial agents, and HTA needs methods to incorporate this
additional value in their assessments.
A further complication is that, for reimbursement purposes, we
need to put a value on having antimicrobial agents available now
for the resistant pathogens that will cause outbreaks in the future,
so that they are available when needed.42 We hope, though, that
health systems will not actually use these doses for many years.
New antimicrobial agents may also provide value by enabling
surgical procedures and cancer chemotherapy to take place,
providing a more diverse portfolio of options to treat infectious
disease, or through other characteristics that are unique compared
with other types of medical technologies,43-46 sometimes referred
to with the acronym “STEDI”—spectrum, transmission,
enablement, diversity, and insurance (Table 2). The use of
antimicrobial agents also results in a negative externality, because
increasing consumption results in increasing selection pressure
for resistance.47,48 Ignoring this negative externality leads to the
overconsumption of currently available antimicrobial agents,
which increases the problem of resistance and thus the need for
additional novel treatments.
The default framework for thinking about disease in HTA
agencies has been a noncommunicable disease (NCD) paradigm,
focused on benefits accrued to an individual patient, which misses
these broader benefits of antibiotic agents. This is reflected in the
orientation of the core HTA methodology texts and United
Kingdom National Institute for Health and Care Excellence (NICE)
methods guidance, which have no or sparse mention of antibiotic
agents, antimicrobial agents, communicable disease, and
infectious disease.49-52 Furthermore, the NICE Guide section on
“time horizon” focuses on whether the time horizon of modeling
should be the lifetime of the patient receiving treatment or
shorter, but, from an infectious disease point of view, the time
horizon may be longer than the patient’s life. Nevertheless, the
National Immunization Technical Advisory Groups such as
the UK’s Joint Committee on Vaccination and Immunisation and
1830 VALUE IN HEALTH DECEMBER 2021
Table 1. High-level political action on antimicrobial resistance.
Year Action
2015 World Health Assembly (the governing body of the WHO) agrees to a resolution on AMR and adopts a Global Action Plan on
AMR.19
2015 The G7 health ministers agree to a declaration on AMR.20
2016 World leaders commit to the struggle against AMR at the UN General Assembly (1 of only 4 occasions on which a health issue
has been addressed in this forum).21
2017 The G20 health ministers, meeting for the first time, address the importance of international cooperation on AMR.22
2017-2020 G20 leaders consider AMR for 4 consecutive years.23-26 In 2019, G20 leaders specifically highlight the need for push and pull
incentives to promote R&D in antimicrobial agents.
2019 G20 health and finance ministers meet together for the first time, discussing AMR.27
2020 Launch of the One Health Global Leaders Group on Antimicrobial Resistance by the WHO, the FAO of the UN, and OIE28
AMR indicates antimicrobial resistance; FAO, Food and Agriculture Organization; OIE, World Organisation for Animal Health; R&D, research and development;
UN, United Nations; WHO, World Health Organizationthe US Preventive Services Task Force do often incorporate
economic evaluations that capture community-wide externalities
in developing their recommendations, demonstrating that it is
feasible to adapt economic evaluation methods to the special
characteristics of infectious diseases.53,54 A recent discussion
around expanding the concept of what constitutes “value” in HTAs
more broadly55 also captures some of the elements that are
important for antibiotic agents (risk of contagion and insurance),
but not all.
There is some appreciation at policy levels of the importance of
taking into account transmission benefits and the other unique
benefits of antimicrobial agents alongside the negative externality
associated with consumption. In the United Kingdom, for
example, the government has committed to developing and
testing a new antibiotic “subscription” purchasing model for 2
products based on revised assessment methods.56,57 The model
will consist primarily of annual lump-sum payments based on a
product’s value to the National Health Service rather than the
number of doses sold, rewarding companies based on the full
range of benefits provided by the product and recognizing that
basing pharmaceutical companies’ revenue for antimicrobial
products on the number of doses sold does not provide
appropriate incentives for stewardship. Nevertheless, although
similar subscription models have been proposed in the United
States58,59 and some national HTA agencies show an awareness of
the issues surrounding antimicrobial agents, there are fewer signs
of practical actions and less consideration being given to how
these issues might impact payment models,40,60 although Norway
has taken a first step in allowing the societal value of AMR to be
included in HTA.61 In the United Kingdom, the evaluation
framework is under active development with NICE for the critical
question of how a reasonable fixed price can be determined.45,62
Such a price must be sufficient to incentivize innovation, but
also, in keeping with value-based pricing philosophy, represent
good value for the taxpayer who is the ultimate payer in a
single-payer healthcare system.Deficiencies of Current HTA Processes for
Appraising New Antimicrobial Technologies
In our view, there are 3 main shortcomings in current HTA
process: a methods-centric rather than problem-centric approach
to dealing with new challenges, a lack of tools for thinking about
the changing pattern of infection and resistance, and the absence
of an approach to epidemiological risks. We expand on each in
turn:Methods-Centric Rather Than Problem-Centric Approach
to Dealing With New Challenges
HTA has developed its methodological armory over recent
decades, but a danger with proficiency in a fixed armory is that
elements of the problem are ignored because they are not easily
handled with that armory. We argue this is the case for AMR.
Challenges designing randomized control trials for antimicrobial
agents make determining the patient-level clinical effectiveness of
a new antimicrobial for resistant infections difficult,63-65 and
gauging an antimicrobial’s population-level effectiveness cannot
easily be done with trial data. Indeed, even assessing the baseline
risk of a resistant outbreak is far from trivial: this risk cannot be
readily read off or extrapolated from available epidemiological
data. Furthermore, trials designed for registration of a new
product may not reflect the variety of ways clinicians will use the
technology in practice, so HTA bodies may need to think more
broadly about a product’s use and consider additional data
sources, such as pharmacokinetic/pharmacodynamic data and
pragmatic trials, cluster randomized trials, observational data, and
other studies that capture the real-world effects of treatment,
where applicable.44
Lack of Tools for Thinking About the Changing Pattern of
Infection
As noted earlier, HTA agencies’ methods expertise tends to
focus on NCDs. Nevertheless, most infectious disease models are
population level, making them different from the models used for
NCDs. For example, infectious disease models (1) generally have
more parameters because they include contacts and transmission
between individuals in addition to disease progression within the
individual, (2) are difficult to validate because the unit of analysis
is the population, and (3) have nonlinear model dynamics.
Modeling the spread of resistant pathogens is particularly
challenging because a critical determinant of the spread of
resistance is the “fitness cost” associated with the resistance
mechanism, and for many resistance mechanisms, this is not well
understood. The expertise to interpret models of infectious
diseases may lie not with HTA agencies but with other
government agencies such as public health agencies and their
advisory committees (such as the Joint Committee on Vaccination
and Immunisation and the Advisory Committee on Antimicrobial
Prescribing, Resistance and Healthcare Associated Infection in the
United Kingdom). Hence, HTA agencies should build their capacity
in this area but also partner with research and policy institutes
and programs who can generate and interpret the fundamental
scientific knowledge on which such modeling depends.
POLICY PERSPECTIVE 1831
Table 2. The “STEDI” values of antimicrobial agents.
Values Description
Spectrum Reducing unintended impacts on the microbiome through moving from broad- to narrow-spectrum antimicrobial agents
Transmission Reducing spread to other individuals through effective treatment
Enablement Providing access to medical treatments and procedures through effective prophylaxis
Diversity Reducing selection pressure on pathogens by increasing the range of treatment options available
Insurance Preparing for future increases in the prevalence of resistant infections by developing new antimicrobial agents now
Note. Adapted from Rothery et al45 and Outterson and Rex.46
STEDI indicates spectrum, transmission, enablement, diversity, and insurance.Absence of an Approach to Epidemiological Risks
A persistent theme in health economics is the difficulty of
assessing the quality of medical care. This expresses itself in
HTA through a heightened awareness of the high cost of
obtaining information about the effectiveness of a medical
technology. Hence, as the field has matured, we have seen an
emphasis on characterizing the uncertainty in the evidence
base and making provisional decisions which get promising
technologies into the hands of patients, while simultaneously
generating additional evidence. Nevertheless, the risks in the
area of antimicrobial agents are different in nature from the risk
that, say, an antihypertensive may perform worse in the clinical
setting than the trial setting: they are what could be called
“epidemiological risks.” The risks of poor clinical performance
can, in principle, be reduced with larger, better designed, more
representative trials and observational studies; epidemiological
risks (eg, the risk of a new resistance mechanism evolving and
spreading) cannot be reduced in this way, although relevant
information may become available over time via surveillance
systems collating data on resistant infections. As highlighted
earlier, a key reason is that understanding and modeling the
spread of resistance could be called “frontier science.” Even if
we could have perfect data about resistance patterns up to the
present and perfect trial data about the performance of a new
technology (and currently we are far from having either), we
would not know how to extrapolate this information to predict
future resistance trends if the technology were to be deployed.
Nevertheless, despite this uncertainty, we need antimicrobial
agents to provide protection against a potential future
pandemic or rapid change in epidemiology, much as we need
the protection that fire departments and the military provide,
even if future demand for the new technologies proves to be
lower than predicted.41
What Can Be Done?
The shortcomings of HTA agencies identified in the previous
section relate to their capacity to make assessments of new
technologies to combat AMR in particular. HTA agencies perform
an important role in our health systems, and for most of the
technologies they consider (ie, those that apply to NCDs with no
important externalities), their methods are, in our view, fit for
purpose. Furthermore, some of the challenges mentioned, such as
the difficulty developing predictive models that describe the
emergence and transmission of resistant pathogens, are not the
exclusive problem of HTA. Nevertheless, we believe HTA agencies
(including related bodies applying HTA methods to priority setting
in the health sector) could do more to address the shortcomings
identified earlier with respect to the assessment of technologies to
combat AMR. As LMICs increasingly embrace HTA, expanding the
HTA tool kit and broadening the HTA role to appropriately assessvalue for technologies addressing both NCDs and infectious
diseases are increasingly important.
We make the following 3 recommendations.
Recognize a Greater Role for Epidemiological Modeling
and Structured Expert Judgment
Recognizing that methods for extracting more information
from clinical trials and other studies cannot address major residual
uncertainties (eg, surrounding the emergence and spread of
resistance), we suggest that there is a greater role for formal
epidemiological modeling and institutionalizing how expert
judgment is used and quality controlled. For example, some of us
have used Cooke’s Classical Model, which incorporates a method
for weighting experts based on their performance on test
questions,66-68 to elicit expert projections and uncertainty bounds
for resistance rates.69 Of course, relying on expert judgment is a
transitional solution. As science advances, epidemiological models
will be developed that allow us to understand the spread of
resistance with greater confidence than is currently possible. This
requires trials and other studies to collect the endpoints needed in
such models, such as resistance levels and antimicrobial use in the
community. HTA agencies should both express this need to their
sponsoring ministries and also engage with the scientific
community to ensure that science, including the data that
manufacturers are expected to submit in support of their
technologies, evolves to align with the needs of decision makers.
Recognize the Needs of Diverse Stakeholders and
Decision Makers
Challenges such as AMR also raise the question of who is the
customer for HTA. For most technologies, the primary customer
will be healthcare providers or purchasers: they will change
their procedures or purchasing. Nevertheless, AMR poses a
long-term threat that falls under the purview of different sys-
tem actors who control additional funding levers: national
leaders outside the Ministry of Health, international organiza-
tions, and charitable foundations. Addressing these stake-
holders in a way that ensures that messages are given a
sympathetic hearing requires changes in presentation and
building new relationships, and, possibly, institutions. An
example of the lateral thinking this sort of challenge requires is
the blueprint developed by the Center for Global Development
to support an advance market commitment for a new tuber-
culosis regimen.70
Recognize the Role and Value of Supporting Policies and
Targets
Regarding epidemiological risks in the midrange future, we
believe that government health agencies should play a role,
because they can provide expectations of the national resistance
profile. For example, the UK government has announced that it
1832 VALUE IN HEALTH DECEMBER 2021aims to reduce specific drug-resistant infections in the population
by 10% by 2025.71 HTA agencies should recognize that when there
are significant externalities, contributing to these targets is an
important goal that should also be formally factored into
prioritization. Simultaneously, HTA can contribute to an
understanding of whether declared targets are indeed health and
welfare maximizing; a feedback mechanism should exist so that
targets can be adjusted as evidence and understanding advances.
To incentivize appropriate research, HTA agencies should
incorporate in their guidelines explicit recommendations to
capture the community externalities of antimicrobial agents and
other infectious disease interventions where data to inform such
valuations exist.Conclusion
HTA is based on the concept that there should be no “special
pleading”: that the rules should be applied without discrimination
to all health technologies. This impartiality is core to HTA’s
conception of itself. Nevertheless, antimicrobial agents and AMR
pose no challenge to the fundamental principles of HTA; the rules
of HTA—developed primarily with technologies for NCDs in
mind—do a poor job of addressing the particular scientific and
policy challenges that arise in appraising technologies to combat
infectious disease, similar to vaccines.54,72 We believe that HTA
being part of the solution in the struggle against AMR will require
an expansion in the technical tool kit and a change in philosophy.
Otherwise, HTA risks becoming part of the problem, destroying
value and destroying incentives to bring life-saving new
technologies to future populations.Article and Author Information
Accepted for Publication: June 7, 2021
Published Online: September 20, 2021
doi: https://doi.org/10.1016/j.jval.2021.06.002
Author Affiliations: Management Science, Strathclyde Business School,
University of Strathclyde, Glasgow, Scotland, UK (Colson, Morton,
Megiddo); Antimicrobial Resistance Centre, Norwegian Institute of Public
Health, Oslo, Norway (Årdal); School of Public Health, Imperial College
London, London, England, UK (Chalkidou); UK Department of Health and
Social Care, London, England, UK (Davies); The Comparative Health Out-
comes, Policy, and Economics Institute, University of Washington, Seattle,
WA, USA (Garrison); Department of Infectious Disease Epidemiology, Lon-
don School of Hygiene & Tropical Medicine, London, England, UK (Jit);
Center for Disease Dynamics, Economics & Policy, Washington, DC, USA
(Laxminarayan); Institute for Hygiene and Public Health, University Hospi-
tal Bonn, Bonn, Germany (Morel); Department of Business Studies,
Uppsala University, Uppsala, Sweden (Morel); Geneva Transformative
Governance Lab, Science Faculty, University of Geneva, Geneva,
Switzerland (Morel); Department of Health Policy, Planning and Manage-
ment, School of Public Health, University of Ghana, Legon, Ghana (Non-
vignon); School of Law, Boston University, Boston, MA, USA (Outterson);
F2G Limited, Eccles, Cheshire, UK and AMR Solutions, Boston, MA, USA
(Rex); Bangladesh Institute of Development Studies, Dhaka, Bangladesh
(Sarker); Centre for Health Economics, University of York, York, England, UK
(Sculpher, Woods); China National Health Development Research Centre
(National Centre for Medicine and Health Technology Assessment), Beijing,
P. R. China (Xiao).
Correspondence: Abigail Colson, PhD, Management Science, University of
Strathclyde, 199 Cathedral St, Glasgow, Scotland, United Kingdom G4 0QU.
Email: abigail.colson@strath.ac.uk
Author Contributions: Concept and design: Colson, Morton, Garrison, Jit,
Megiddo, Nonvignon, Outterson, Rex, Sculpher, Woods, Xiao
Analysis and interpretation of data: Colson, Morton, Årdal, Chalkidou,Davies, Megiddo, Morel, Sarker
Drafting of the manuscript: Colson, Morton, Årdal, Chalkidou, Davies,
Garrison, Jit, Morel, Nonvignon, Outterson, Rex, Sculpher, Woods, Xiao
Critical revision of the paper for important intellectual content: Colson,
Morton, Årdal, Chalkidou, Davies, Garrison, Jit, Laxminarayan, Megiddo,
Morel, Nonvignon, Outterson, Rex, Sarker, Sculpher, Woods, Xiao
Administrative, technical, or logistic support: Colson, Morton, Laxminarayan,
Sarker Supervision: Colson, Morton, Laxminarayan, Sarker
Other: Outterson
Conflict of Interest Disclosures: Dr Morton reported receiving personal
fees from AstraZeneca and the Office of Health economics; and reported
nonfinancial support from the European Federation of Pharmaceutical
Industries and Associations (consortium of pharmaceutical firms) outside
the submitted work. Dr Årdal reported receiving grants from the European
Union Innovative Medicines Initiative and the European Commission for
European Union Joint Action on Antimicrobial Resistance and Healthcare-
Associated Infections during the conduct of the study. Dr Chalkidou is an
editor for Value in Health and had no role in the peer-review process of this
article. Dr Outterson reported receiving grants from the US Department of
Health and Human Services Biomedical Advanced Research and Devel-
opment Authority, the UK Global Antimicrobial Resistance Innovation
Fund, Germany, BMBF, the Gates Foundation, and the Wellcome Trust
outside the submitted work. Dr Rex reported being Chief Medical Officer
and Director, F2G, Ltd; reported being Editor-in-Chief of Antimicrobial
Resistance Solutions; reported being Operating Partner and Consultant,
Advent Life Sciences, and Adjunct Professor of Medicine, McGovern Med-
ical School, Houston, TX; reported serving on the scientific advisory boards
of Bugworks Research, Inc, Basilea Pharmaceutica, Forge Therapeutics, Inc,
Novo Holdings, and Roche Pharma Research and Early Development; re-
ported receiving consulting fees from Phico Therapeutics, ABAC Thera-
peutics, Polyphor, Ltd, Heptares Therapeutics, Ltd, Gangagen, Ltd, Meiji
Seika Pharma, Basilea Pharmaceutica International Ltd, Allecra Therapeu-
tics GmbH, Forge Therapeutics, Inc, SinSa Labs, AtoxBio, Peptilogics, F.
Hoffmann-LaRoche, Ltd, Novo Holdings, Innocoll, Vedanta, Progenity,
Nosopharm SA, Roivant Sciences, Shionogi Inc, GlaxoSmithKline, and Pfizer
Pharmaceuticals outside the submitted work; reported stock ownership in
AstraZeneca Pharmaceuticals, F2G, Ltd, Advent Life Sciences, Zikani Ther-
apeutis, and Bugworks Research, Inc outside the submitted work. Dr
Sculpher reported receiving grants from the National Institute of Health
Research Policy Research Program during the conduct of the study; and
reported receiving personal fees from various life science companies
outside the submitted work. No other disclosures were reported.
Funding/Support: The authors received no financial support for this work.REFERENCES
1. Teillant A, Gandra S, Barter D, Morgan DJ, Laxminarayan R. Potential burden
of antibiotic resistance on surgery and cancer chemotherapy antibiotic
prophylaxis in the USA: a literature review and modelling study. Lancet Infect
Dis. 2015;15(12):1429–1437.
2. Pragasam AK, Shankar C, Veeraraghavan B, et al. Molecular mechanisms of
colistin resistance in Klebsiella pneumoniae causing bacteremia from India—a
first report. Front Microbiol. 2017;7:2135.
3. Gandra S,Mojica N, Klein EY, et al. Trends in antibiotic resistance amongmajor
bacterial pathogens isolated from blood cultures tested at a large private
laboratory network in India, 2008-2014. Int J Infect Dis. 2016;50:75–82.
4. Guidelines for the treatment of malaria. Third edition. World Health
Organization. https://apps.who.int/iris/bitstream/handle/10665/162441/978
9241549127_eng.pdf;jsessionid=E711513734D05C16402B0CEA30B12267?
sequence=1. Accessed August 19, 2021.
5. Dondorp AM, Nosten F, Yi P, et al. Artemisinin resistance in Plasmodium
falciparum malaria [published correction appears in N Engl J Med.
2009;361(17):1714]. N Engl J Med. 2009;361(5):455–467.
6. Ashley EA, Dhorda M, Fairhurst RM, et al. Spread of artemisinin resistance in
Plasmodium falciparum Malaria [published correction appears in N Engl J
Med. 2014;371(8):786]. N Engl J Med. 2014;371(5):411–423.
7. Woodrow CJ, White NJ. The clinical impact of artemisinin resistance in
Southeast Asia and the potential for future spread. FEMS Microbiol Rev.
2017;41(1):34–48.
8. Tuberculosis: multidrug-resistant tuberculosis (MDR-TB): what is multidrug-
resistant tuberculosis (MDR-TB) and how do we control it? World Health
Organization. http://www.who.int/features/qa/79/en/. Accessed July 12, 2019.
9. Cassini A, Högberg LD, Plachouras D, et al. Attributable deaths and
disability-adjusted life-years caused by infections with antibiotic-resistant
bacteria in the EU and the European Economic Area in 2015: a
population-level modelling analysis. Lancet Infect Dis. 2019;19(1):56–66.
POLICY PERSPECTIVE 183310. Antibiotic resistance threats in the United States, 2019. Centers for Disease
Control and Prevention. https://www.cdc.gov/drugresistance/pdf/threats-
report/2019-ar-threats-report-508.pdf. Accessed August 19, 2021.
11. Jonas OB, Irwin A, Berthe FCJ, Le Gall FG, Marquez PV. Drug-resistant
infections: a threat to our economic future (vol. 2): final report (English). The
World Bank. http://documents.worldbank.org/curated/en/323311493396
993758/final-report. Accessed July 12, 2019.
12. Tackling drug-resistant infections globally: final report and recommenda-
tions: the review on antimicrobial resistance. http://amr-review.org/sites/
default/files/160525_Final%20paper_with%20cover.pdf. Accessed August 11,
2016.
13. Laxminarayan R, Matsoso P, Pant S, et al. Access to effective antimicrobials: a
worldwide challenge. Lancet. 2016;387(10014):168–175.
14. Vaccines to tackle drug resistant infections: an evaluation of R&D
opportunities. Wellcome Trust and The Boston Consulting Group. https://
vaccinesforamr.org/wp-content/uploads/2018/09/Vaccines_for_AMR.pdf.
Accessed August 19, 2021.
15. 2019 Antibacterial agents in clinical development: an analysis of the anti-
bacterial clinical development pipeline. World Health Organization. https://
apps.who.int/iris/bitstream/handle/10665/330420/9789240000193-eng.pdf.
Accessed May 14, 2021.
16. Beyer P, Paulin S. Priority pathogens and the antibiotic pipeline: an update.
Bull World Health Organ. 2020;98(3):151.
17. Theuretzbacher U, Outterson K, Engel A, Karlén A. The global preclinical
antibacterial pipeline. Nat Rev Microbiol. 2020;18(5):275–285.
18. Plackett B. Why big pharma has abandoned antibiotics. Nature.
2020;586(7830):S50–S52.
19. Antimicrobial resistance: draft global action plan on antimicrobial resistance.
Sixty-Eights World Health Assembly, World Health Organization. http://apps.
who.int/gb/ebwha/pdf_files/WHA68/A68_20-en.pdf. Accessed August 19,
2021.
20. Declaration of the G7 Health Ministers 8 – 9 October 2015 in Berlin. G7
Germany 2015 Gesundheitsministertreffen. http://www.bundesgesundhe
itsministerium.de/fileadmin/Dateien/3_Downloads/G/G7/G7_Health_Minis
ters_Declaration_AMR_and_EBOLA.pdf. Accessed April 30, 2017.
21. High-level meeting on antimicrobial resistance. General Assembly of the
United Nations. http://www.un.org/pga/71/event-latest/high-level-meeting-
on-antimicrobial-resistance/. Accessed April 30, 2017.
22. Berlin Declaration of the G20 Health Ministers: Together Today for a Healthy
Tomorrow. G20 Germany 2017. https://www.bundesgesundheits
ministerium.de/fileadmin/Dateien/3_Downloads/G/G20-Gesundheitsminister
treffen/G20_Health_Ministers_Declaration_engl.pdf. Accessed July 14, 2019.
23. G20 leaders’ declaration: shaping an interconnected world. G20 Germany
2017 Hamburg. https://www.oecd.org/els/health-systems/G20-leaders-
declaration.pdf. Accessed July 14, 2019.
24. G20 leaders’ declaration: building consensus for fair and sustainable
development. G20 Argentina 2018. https://www.consilium.europa.eu/
media/37247/buenos_aires_leaders_declaration.pdf. Accessed August 19,
2021.
25. The G20 Osaka Leaders’ Declaration. https://www.mofa.go.jp/policy/econ
omy/g20_summit/osaka19/en/documents/final_g20_osaka_leaders_declarati
on.html. Accessed August 19, 2021.
26. Leaders’ declaration: G20 Riyadh summit. G20 Saudi Arabia Riyadh Summit.
https://www.consilium.europa.eu/media/46883/g20-riyadh-summit-leaders-
declaration_en.pdf. Accessed February 5, 2021.
27. Chancellor urges global action to tackle antimicrobial resistance crisis. GOV.
UK. Published June 28. https://www.gov.uk/government/news/chancellor-
urges-global-action-to-tackle-antimicrobial-resistance-crisis. Accessed July
14, 2019.
28. World leaders join forces to fight the accelerating crisis of antimicrobial
resistance. World Health Organization. https://www.who.int/news/item/2
0-11-2020-world-leaders-join-forces-to-fight-the-accelerating-crisis-of-
antimicrobial-resistance. Accessed February 5, 2021.
29. Outterson K, Rex JH, Jinks T, et al. Accelerating global innovation to address
antibacterial resistance: introducing CARB-X. Nat Rev Drug Discov.
2016;15(9):589–590.
30. CARB X. https://carb-x.org/. Accessed September 30, 2020.
31. Novo Holdings launches USD 165m impact fund to combat antimicrobial
resistance. REPAIR Impact Fund. https://www.repair-impact-fund.com/news-
folder/repair-launch/. Accessed July 15, 2019.
32. Piddock LJV, GARDP. The global antibiotic Research and Development Part-
nership (GARDP): a not-for-profit antibiotic development organisation. Lan-
cet Infect Dis. 2018;18(12):1304–1305.
33. Piddock LJV. The global antibiotic research and development partnership
(GARDP): researching and developing new antibiotics to meet global public
health needs. Med Chem Commun. 2019;10(8):1227–1230.
34. Antibiotics Biotech firms are struggling. The Economist; May 2, 2019. https://
www.economist.com/business/2019/05/02/antibiotics-biotech-firms-are-
struggling. Accessed July 15, 2019.
35. Zemdri: withdrawal of the marketing authorisation application. European
Medicines Agency. https://www.ema.europa.eu/en/medicines/human/
withdrawn-applications/zemdri. Accessed September 30, 2020.36. Nuzyra: withdrawal of the marketing authorisation application. European
Medicines Agency. https://www.ema.europa.eu/en/medicines/human/
withdrawn-applications/nuzyra. Accessed October 20, 2020.
37. Rex J, Outterson K. New antibiotics are not being registered or sold in Europe
in a timely manner. AMR.Solutions. https://amr.solutions/2020/09/07/new-
antibiotics-are-not-being-registered-or-sold-in-europe-in-a-timely-
manner/. Accessed October 20, 2020.
38. Tantivess S, Chalkidou K, Tritasavit N, Teerawattananon Y. Health Technology
Assessment capacity development in low- and middle-income countries:
experiences from the international units of HITAP and NICE. F1000Research.
2017;6:2119.
39. MacQuilkan K, Baker P, Downey L, et al. Strengthening health technology assess-
ment systems in the global south: a comparative analysis of the HTA journeys of
China, India and South Africa. Glob Health Action. 2018;11(1):1527556.
40. Morton A, Colson A, Leporowski A, Trett A, Bhatti T, Laxminarayan R. How
should the value attributes of Novel antibiotics be considered in
reimbursement decision making? MDM Policy Pract. 2019;4(2):
2381468319892237.
41. Rex JH, Outterson K. Antibiotic reimbursement in a model delinked from
sales: a benchmark-based worldwide approach. Lancet Infect Dis.
2016;16(4):500–505.
42. Megiddo I, Drabik D, Bedford T, Morton A, Wesseler J, Laxminarayan R.
Investing in antibiotics to alleviate future catastrophic outcomes: what is the
value of having an effective antibiotic to mitigate pandemic influenza? Health
Econ. 2019;28(4):556–571.
43. Årdal C, Findlay D, Savic M, et al. Revitalizing the antibiotic pipeline:
stimulating innovation while driving sustainable use and global access.
Drive-AB Report. http://drive-ab.eu/wp-content/uploads/2018/01/DRIVE-AB-
Final-Report-Jan2018.pdf. Accessed July 25, 2019.
44. Karlsberg Schaffer S, West P, Towse A, et al. Assessing the value of new
antibiotics: additional elements of value for health technology assessment
decisions. Office of Health Economics. https://www.ohe.org/system/files/
private/publications/OHE%20AIM%20Assessing%20The%20Value%20of%20
New%20Antibiotics%20May%202017.pdf. Accessed July 22, 2019.
45. Rothery C, Woods B, Schmitt L, Claxton K, Palmer S, Sculpher M. Framework
for value assessment of new antimicrobials: implications of alternative
funding arrangements for NICE appraisal. Policy Research Unit in Economic
Evaluation of Health & Care Interventions. http://www.eepru.org.uk/wp-
content/uploads/2017/11/eepru-report-amr-oct-2018-059.pdf. Accessed
August 19, 2021.
46. Outterson K, Rex JH. Evaluating for-profit public benefit corporations as an
additional structure for antibiotic development and commercialization.
Transl Res. 2020;220:182–190.
47. Coast J, Smith RD, Millar MR. An economic perspective on policy to reduce
antimicrobial resistance. Soc Sci Med. 1998;46(1):29–38.
48. Laxminarayan R, Brown GM. Economics of antibiotic resistance: a theory of
optimal use. J Environ Econ Manag. 2001;42(2):183–206.
49. Drummond MF, Sculpher MJ, Claxton K, et al. Methods for the Economic
Evaluation of Health Care Programmes. 4th ed. Oxford, United Kingdom:
Oxford University Press; 2015.
50. Neumann PJ, Ganiats TG, Russell LB, Sanders GD, Siegel JE, eds. Cost
Effectiveness in Health and Medicine. 2nd ed. Oxford, United Kingdom: Oxford
University Press; 2016.
51. Guide to the methods of technology appraisal 2013. National Institute for
Health and Care Excellence. https://www.nice.org.uk/process/pmg9/
resources/guide-to-the-methods-of-technology-appraisal-2013-pdf-2007
975843781. Accessed August 19, 2021.
52. Stevenson MD, Oakley JE, Chick SE, Chalkidou K. The cost-effectiveness of
surgical instrument management policies to reduce the risk of vCJD
transmission to humans. J Oper Res Soc. 2009;60(4):506–518.
53. Gessner BD, Duclos P, DeRoeck D, Nelson EA. Informing decision makers:
experience and process of 15 National Immunization Technical Advisory
Groups. Vaccine. 2010;28(suppl 1):A1–A5.
54. Beutels P, Scuffham PA, MacIntyre CR. Funding of drugs: do vaccines warrant
a different approach? Lancet Infect Dis. 2008;8(11):727–733.
55. Lakdawalla DN, Doshi JA, Garrison LP, Phelps CE, Basu A, Danzon PM.
Defining elements of value in health care—a health economics approach: an
ISPOR Special Task Force Report [3]. Value Health. 2018;21(2):131–139.
56. Development of new antibiotics encouraged with new pharmaceutical
payment system. GOV.UK, Department of Health & Social Care. https://www.
gov.uk/government/news/development-of-new-antibiotics-encouraged-
with-new-pharmaceutical-payment-system. Accessed January 19, 2021.
57. Perkins M, Glover D. How the ‘NHS model’ to tackle antimicrobial resistance
(AMR) can set a global standard. NHS. https://www.england.nhs.uk/blog/
how-the-nhs-model-to-tackle-antimicrobial-resistance-amr-can-set-a-glo
bal-standard/. Accessed January 19, 2021.
58. Schneider M, Daniel GW, Harrison NR, McClellan MB. Delinking US antibiotic
payments through a subscription model in Medicare. Duke-Margolis Center
for Health Policy. https://healthpolicy.duke.edu/sites/default/files/2020-02/
margolis_subscription_model_14jan2020.pdf. Accessed August 19, 2021.
59. The PASTEUR Act. S. 4760 (116th). https://www.govtrack.us/congress/
bills/116/s4760. Accessed August 19, 2021.
1834 VALUE IN HEALTH DECEMBER 202160. Gotham D, Moja L, van der Heijden M, Paulin S, Smith I, Beyer P.
Reimbursement models to tackle market failures for antimicrobials:
approaches taken in France, Germany, Sweden, the United Kingdom, and the
United States. Health Policy. 2021;125(3):296–306.
61. Bayar C, Forland F, Kvalheim C, et al. Utredning Av Hvordan
Smittevernhensyn Og Antimikrobiell Resistens (AMR) Skal Ivaretas i
Metodevurderinger Ved Vurdering Av Offentlig Finansiering. Statens
legemiddelverk. https://legemiddelverket.no/Documents/Offentlig%20finan
siering%20og%20pris/Dokumentasjon%20til%20metodevurdering/Rapport%20-
%20Smittevern%20og%20resistens%20i%20metodevurderinger.pdf.
62. Models for the evaluation and purchase of antimicrobials. National Institute
Health and Care Excellence. https://www.nice.org.uk/about/what-we-do/
life-sciences/scientific-advice/models-for-the-evaluation-and-purchase-of-
antimicrobials. Accessed January 19, 2021.
63. Powers JH, Evans SR, Kesselheim AS. Studying new antibiotics for multidrug
resistant infections: are today’s patients paying for unproved future benefits?
BMJ. 2018;360:k587.
64. Rex JH, Talbot GH, Goldberger MJ, et al. Progress in the fight against
multidrug-resistant bacteria 2005-2016: modern noninferiority trial designs
enable antibiotic development in advance of epidemic bacterial resistance.
Clin Infect Dis. 2017;65(1):141–146. Accessed August 19, 2021.
65. Rex JH. In praise of non-inferiority. AMR.Solutions. https://amr.solutions/202
0/09/19/in-praise-of-non-inferiority/. Accessed January 19, 2021.66. Cooke RM. Experts in Uncertainty: Opinion and Subjective Probability in
Science. Oxford, United Kingdom: Oxford University Press; 1991.
67. Quigley J, Colson A, Aspinall W, Cooke RM. Elicitation in the classical
model. International Series in Operations Research & Management Science.
In: Dias LC, Morton A, Quigley J, eds. ElicitationBerlin, Switzerland:
Springer; 2018:15–36.
68. Colson AR, Cooke RM. Expert elicitation: using the classical model to validate
experts’ judgments. Rev Environ Econ Policy. 2018;12(1):113–132.
69. Colson AR, Megiddo I, Alvarez-Uria G, et al. Quantifying uncertainty
about future antimicrobial resistance: comparing structured expert
judgment and statistical forecasting methods. PLoS One. 2019;14(7):
e0219190.
70. Silverman R. The world needs better drugs for TB. We have a proposal—and
we need your feedback. Center for Global Development. https://www.cgdev.
org/blog/world-needs-better-drugs-tb-we-have-proposal-and-we-need-
your-feedback. Accessed September 30, 2020.
71. Tackling Antimicrobial Resistance 2019–2024: The UK’s Five-Year National
Action Plan. https://assets.publishing.service.gov.uk/government/uploads/
system/uploads/attachment_data/file/784894/UK_AMR_5_year_national_action
_plan.pdf. Accessed August 19, 2021.
72. Brassel S, Neri M, O’Neill P, Steuten L. Realising the broader value of vaccines
in the UK. Office of Health Economics. https://www.ohe.org/publications/
realising-broader-value-vaccines-uk. Accessed January 5, 2021.