This document discusses the role of health technology assessment (HTA) and contracting mechanisms for new antibiotic drugs to address antimicrobial resistance (AMR). It notes that HTA typically focuses on clinical trial evidence but this presents challenges for antibiotics. The document recommends that HTA for antibiotics consider additional elements of public health value and that contracting move away from volume-based payments towards delinked models. International coordination on developing new approaches to AMR drug assessment and reimbursement is encouraged.

1. ohe.org
HTA and payment mechanisms for
new drugs to tackle AMR
AMR R&D HUB
31 OCTOBER 2019 - PARIS
Adrian Towse

2. Agenda
1. Project objectives
2. The role of HTA and contracting
3. HTA and contracting for antibiotics
4. What constitutes value for antibiotics?
5. Measuring and modelling antibiotic value
6. Innovative payment models
7. Conclusions and recommendations
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3. 1. Project objectives
● Review of recent proposals in the literature for changing HTA and contracting for antibiotics
● What constitutes value for antibiotics?
● Modelling antibiotic value
● Innovative payment models
● Comparison with current state of HTA and contracting for antibiotics in France, Germany, Italy,
Sweden, and the UK
● Recommendations on the future of antibiotics HTA and contracting, developed following a
programme of interviews and a Forum on ‘Value Assessment and Contracting for Antibiotics’
● This research was commissioned and funded by the Wellcome Trust
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4. 2. The role HTA and contracting
● Most national health systems undertake some form of value assessment of a new drug before providing or reimbursing it for patients
● Value assessment of new drugs is typically based around evidence from randomised controlled trials (RCTs)
● Given the value assessment, health systems decide if the price charged by manufacturers is justified, or what price they would be willing to pay,
for all or some of the label indications of the new drug
● Manufacturers are generally then paid an agreed price per pill
● Deals may be struck on the ‘list’ price, taking account of expectations or limits on prescribing, of volume and sometimes of outcomes
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5. 3. HTA and contracting for antibiotics
● Value assessment of new drugs is typically based around RCTs to show clinical superiority against a comparator treatment. This is a problem for
new antibiotics because:
● Estimates of effectiveness in patients to be treated are typically based on non-superiority trials
● Non-clinical data (such as PK/PD and in-vitro microbiological data) are typically not accepted by HTA agencies
● A considerable part of antibiotic value arises from externalities (benefits and costs to the non-treated individuals) which are not measured in RCTs
● The treatment strategies which will maximise value to patients and the wider public are not considered in RCTs
● Most pricing & reimbursement arrangements agree a price per pill. This is a problem for new antibiotics because:
● Stewardship arrangements limit use of the drug during the period of patent protection to optimise long term social value
● Low volumes will not provide a return on investment for developers
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6. 4. What constitutes value for antibiotics?
● A considerable part of antibiotic value arises from ‘externalities (e.g. transmission of infections, impact on rate of growth of AMR)
● Conventional HTA methods only include the effects associated with treating the immediate patient
● Examples of consideration in deliberative decision making, but no formal for AMR-related HTA assessment (e.g. France)
● Recent legislation in Germany has established that AMR can be considered as an additional value element of antibiotics, but not
clear how this will be applied in practice
● Previous work by OHE (Karlsberg Schaffer et al., 2017) made the case for going beyond the benefits of antibiotics typically
considered in HTA (i.e. health gains and cost offsets, and in some systems also unmet need, and productivity benefits) and
identified public health benefits that are relevant to the health system and wider society but are not considered in traditional
assessments
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7. 7
REACTIONS & RECOMMENDATIONS
● The typically ‘not included’ elements of
antibiotics appear to be important
● More research on avoiding double counting
and value measurement approaches
● To progress the inclusion of the value
elements, start from value dimensions that
have the greatest impact on overall value,
and for which it is possible to generate
evidence of value on
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Transmission value
Arises from preventing the spread of the infection
among the wider population by treating individual patients
Enablement value
Arises if from protecting the safety profile of surgical
procedures that rely on prophylactic or post-operation
antibiotic interventions
Diversity value
Arises where from attenuating the ‘selection pressure’ on
existing antibiotics and preserve the efficacy of these
exiting treatments against resistant pathogens
Insurance value
Arises from having access to an effective treatment
available in case of a catastrophic event, such as an
outbreak of multi-drug resistant pathogen
Novel action value
Arises from preventing cross-resistance among classes
of antibiotics, and fostering R&D of ‘follow-on’ products
with the same mechanism of action
Spectrum value
Emerges from antibiotics that cover a narrower spectrum
of pathogens, preventing the ‘collateral damage’ to the
microbiome and reducing the build-up of AMR
Unmet need Productivity benefits
Health gains Cost offsets
TYPICALLY
INCLUDEDTYPICALLYNOTINCLUDED
4. What constitutes value for antibiotics?

8. 5. Measuring and modelling antibiotic value
● Proposals to model the value of the public health benefits of antibiotics in HTA using QALYs and estimates of cost-
effectiveness in:
● Morton et al. (forthcoming) - recommendations to modify incremental cost-effectiveness ratios (ICERs) in order to
capture the public health effects of antibiotics
● Rothery et al. (2018) - approach for a comprehensive assessment, including consideration of relevant strategies for
antibiotic use and estimation of population benefits using dynamic models to simulate the dynamics of resistance
transmission and development
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9. 5. Measuring and modelling antibiotic value
REACTIONS & RECOMMENDATIONS
● Proposals rely on complex modelling exercises that require advanced expert capabilities for their implementation
● Adequate expert capacity may be available in the UK, but progress is needed to build it up in other countries
● Scarcity of data on AMR transmission and development
● Potential role of clinicians, epidemiologists and other experts judgement where data are missing or to simplify the estimation of resistance
trends and other key parameters
● Importance of using a perspective of analysis that captures appropriately the public health benefits of antibiotics
● Standard HTA methods rely on evidence from RCTs. These typically do not demonstrate clinical superiority of new antibiotics, and are site based
rather than pathogen based
● Appropriate antibiotic value should be modelled according to the clinically relevant strategies of use (typically pathogen based) and to
estimate of clinical value based on PK/PD data and expert opinion
● Some elements of antibiotic value (e.g. transmission value) are already applied to vaccines assessment
● The modelling expertise of certain member state agencies in charge of assessing vaccines (e.g. France, Germany and England) could be used to
assess the value of characteristics that are shared by vaccines and antibiotics
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10. 6. Innovative payment models
● The contracting of antibiotics is usually regulated through tariff-based payments (DRGs), which disincentivises the optimal use of new
antibiotics if their value is reflected in a high price
● Proposals for antibiotic contracting in terms of models that delink payments from volume sold, in order
to provide appropriate R&D reward while promoting stewardship:
● Daniel et al. (2017) propose a Priority Antimicrobial Value Entry (PAVE) award, consisting of a pre-set
market entry reward available upon launch, and a progressive shift towards value-based contracts
● Little discussion to date on novel contracting for antibiotics, it is unclear whether delinked payment models will be considered because they
represent a major departure from existing contracting approaches. Some progress in:
● the UK - NICE and NHS England have recently announced a pilot programme of a delinked payment-based system
● Sweden - pilot of lump sum payment model, but this initiative seems to address the availability of antibiotics in the Swedish market rather
than providing appropriate R&D incentives
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11. Governments should promote change of antibiotics assessment and contracting with internationally coordinated initiatives.
EUnetHTA for example, or successor bodies, could be tasked with a role in developing a joint assessment of a new antibiotic,
thus hopefully stimulating independent action.
Countries gaining experience with innovative HTA and contracting for antibiotics (UK) should
share the learnings with other countries to contribute to the common understanding of
the most effective policy interventions
7. Conclusions and recommendations
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Governments and funding institutions should continue to advocate change to HTA
and contracting for antibiotics around the world, particularly within Europe

12. In the short-term, new antibiotics should be excluded from DRG-bundled payments to disincentivise the use of cheaper
drugs.
‘Volume-delinked’ payments may instead represent a longer-term solution because these schemes encourage
better adherence to stewardship.
There is an overlap between the elements of value that are relevant for vaccines and antibiotics.
The advanced vaccines modelling approaches could be transferred to antibiotics to model the patterns of
transmission and herd immunity
Antibiotic value should be determined on consideration of actual strategies of usage,
even if these differ markedly from those tested in registration trials
The elements of value that are most relevant for particular types of antibiotics and usage
scenarios should be identified and expert elicitation should be used to inform
modelling
7. Conclusions and recommendations
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14. Appendix

15. The role of HTA and contracting for antibiotics
● The antibiotics available today are becoming obsolete at a fast pace, and industry development pipelines of antibiotics are weak
● The development of antibiotics faces a threefold challenge:
● Scientific - due to the low success rates in R&D stages
● Regulatory and Clinical - due to the challenges of generating evidence of clinical superiority in randomised controlled trial (RCT)
● Economic - due to the low expected returns on investments (ROI) from antibiotic sales
● A number of interventions have been proposed to antibiotics R&D:
● Push incentives - providing financial and scientific support the development of new antibiotics
● Pull incentives – providing rewards to manufacturers for bringing to market new antibiotics (e.g. market entry rewards, volume-delinked payment
models)
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16. 16
● Push incentives alone will not be sufficient to
stimulate investments in antibiotic innovation
(Ferraro, 2017; Towse et al., 2017), and the
necessary pull incentive to bring the desired
number of antibiotics to the market is large
(O’Neill, 2016; Towse et al., 2017)
● HTA should appropriately recognise the value of
antibiotics to ensure that the price paid (i.e. pull
incentive) is commensurate to their value to the
health system and society
● Payment models (i.e. pull incentive) should also
be aligned with stewardship to optimise the
expected health gains over the useful life of the
antibiotic
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Low discovery and
success rates in
R&D
Scarce evidence
of clinical
superiority in
RCTs
Low return on
investment
Scientific Regulatory & Clinical Economic
Price limited to that of
existing treatments
HTA methods do not
consider ABs public
health value
Stewardship restrict
volume usage to
preserve ABs
effectiveness
Push
incentives
Pull
incentives
HTA
recognising
ABs public
health value
CHELLENGESDRIVERS
POLICY
INTERVENTIONS
to inform