DNA nucleotides Blast in NCBI and Phylogeny using MEGA Xi.pptx
Towse 2020 antimicrobials melbourne final
1. “ANTIMICROBIALS 2020”
27 FEBRUARY 2020, MELBOURNE
Adrian Towse
Emeritus Director & Senior Research Fellow, OHE
Visiting Professor, London School of Economics
2. 1. Acknowledgements
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
● UK proposals by NICE and NHS England
7. Conclusions and recommendations
● Options for Australia
8. References
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ANTIMICROBIALS 2020
3. 27 FEBRUARY 2020
ANTIMICROBIALS 2020
Research funded by the
Wellcome Trust
Research with the
Academy of Infection
Management, funded by
GSK, MSD, and Roche
Research undertaken with AZ
and funded by AZ
The Office of Health Economics
is a not-for-profit (charity). It is
owned by the ABPI but operates
independently.
This trip is funded by MSD.
4. ● 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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5. ● 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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6. ● 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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7. ● 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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8. WAY FORWARD: KEY POINTS
● The typically ‘not included’
elements of antibiotics appear to
be much larger than the immediate
health gain to the patient
● Research is needed to improve
value measurement approaches to
these, and avoid double counting
● Begin with the inclusion of the
value elements that have the
greatest impact on overall value,
and for which it is possible to
generate evidence of value
● Expert elicitation will be crucial to
get (i) agreement on strategy for
optimal use of a drug and (ii)
estimates to inform assessment of
‘not included’ elements of value.
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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, for example, from protecting the safety
of surgical procedures that rely on prophylactic
or post-operation antibiotics, or of using drugs
that suppress the immune system risking
infection
Diversity value
Arises from attenuating the ‘selection
pressure’ on existing antibiotics and
preserving the efficacy of these existing
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
9. ● 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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10. REACTIONS & RECOMMENDATIONS
● Proposals rely on complex modelling exercises that require advanced expert capabilities for their implementation
● Adequate expert capacity may be available in some countries (e.g., UK and Australia), 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 expert 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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11. ● 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
● US CMS NTAP process now reimburses 75% of price of a novel antibiotic outside of DRG, but this does not address
low volumes and need for stewardship
● Proposals from Duke-Margolis 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
● Schneider et al. (2020) propose a subscription model for the public sector (Medicare) patients
● Little discussion to date in Europe 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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12. ● Overall objective is to put in place a subscription model for purchasing antibiotics and ensure
that learnings are shared with the international community.
● Three elements
1. Selection of candidate drugs: Pilot of 2 drugs, one new and one existing, will be separate procurement lots,
use of procurement through “competitive dialogue”
2. Valuation: Use of modified NICE HTA processes with expert opinion to estimate range of ££ value; add to health
gain, cost savings, AMR specific elements of diversity; transmission; enablement; spectrum benefits; and
insurance benefits. Use of pre-clinical data (e.g. PK/PD data) to estimate health gain of the new drug.
3. Contracting: Expected to be fully delinked subscription model, with pre-agreed payments but linked to delivery of
data and of product when needed. Period not yet specified, but could be 5 years, renewable with new data.
● Timing: AMR 5 year vision launched January 2019, Pilot launched July 2019; Stakeholder update Nov 2019; draft
documents expected March 2020; selection by end 2020; valuations by end 2021; contracts negotiated in parallel,
expected end Q1 2022.
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13. Governments should promote change in 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 should share the learnings with other countries to contribute to
the common understanding of the most effective policy interventions
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Governments and funding institutions should continue to advocate
change to HTA and contracting for antibiotics around the world.
14. In the short-term, new antibiotics should be excluded from DRG-bundled payments to
disincentivise the use of cheaper drugs.
‘Volume-delinked’ payments 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
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15. ● Like UK, Australia has high quality HTA valuation expertise for new vaccines and for new drugs
● Experience of “Netflix” style subscription model for Hep.C DAA drugs indicated to rest of the world Australia’s ability to
undertake innovative contracting arrangements
● Opportunity to introduce a subscription model along the broad lines of the UK approach of three elements:
● Selection process for candidates (UK planning 2 products initially)
● Valuation process – recognition that expert opinion will inform conventional HTA approaches, need for ad hoc
approaches whilst more detailed approaches are developed
● Contracting – multi-year “delinked” contract with obligation to supply in line with clinical protocols that enforce
appropriate stewardship of existing and new antibiotics
● Challenge of Federal versus State funding for hospital drugs. Comparable in some ways to UK challenge of decentralised
hospital contracts and NHS finances with a national subscription contract.
● The more experience the international community develops of contracting for new antibiotics, the sooner we will learn
how to get this right.
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16. ● Daniel et al. 2017. Value-based strategies for encouraging new development of antimicrobial drugs. Duke-Margolis Center
for Health Policy. Available at: https://healthpolicy.duke.edu/PAVE
● Dept of Health and Social Care. Jan 2019 Tackling antimicrobial resistance 2019 to 2024: the UK's 5-year national action
plan. Available at
https://assets.publishing.service.gov.uk/government/uploads/system/uploads/attachment_data/file/784894/UK_AMR_5
_year_national_action_plan.pdf
● Dept of Health and Social Care.. Development of new antibiotics encouraged with new pharmaceutical payment system.
News story. July 2019. Available at https://www.gov.uk/government/news/development-of-new-antibiotics-encouraged-
with-new-pharmaceutical-payment-system
● Karlsberg Schaffer, S., West, P., Towse A., Henshall C., Mestre-Ferrandiz J., Masterton R., and Fischer, A. Assessing the
Value of New Antibiotics: Additional Elements of Value for Health Technology Assessment Decisions. Office of Health
Economics Research Paper, May 2017Available at
https://www.ohe.org/system/files/private/publications/OHE%20AIM%20Assessing%20The%20Value%20of%20New%20
Antibiotics%20May%202017.pdf
● Neri, M., Hampson, G., Henshall, C. and Towse, A., 2019. HTA and payment mechanisms for new drugs to tackle AMR.
Available at https://www.ohe.org/publications/hta-and-payment-mechanisms-new-drugs-tackle-amr
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17. ● NICE and NHS England. Nov. 2019 Slide Deck for Stakeholders. Developing and testing innovative models for the
evaluation and purchase of antimicrobials. Available at http://amr.solutions/wp-content/uploads/99/2019-11-25_nhs-
nice_webinar_slides_-_draft_for_release.pdf
● Rothery et al. (2018). FRAMEWORK FOR VALUE ASSESSMENT OF NEW ANTIMICROBIALS. Implications of alternative
funding arrangements for NICE Appraisal. NIHR Policy Research Unit in Economic Evaluation of Health & Care
Interventions (EEPRU). Available at http://www.eepru.org.uk/wp-content/uploads/2017/11/eepru-report-amr-oct-2018-
059.pdf
● Schneider M. et al. February 17, 2020. Delinking US Antibiotic Payments through a Subscription Model in Medicare. Duke-
Margolis Center for Health Policy. Health Affairs blog. Available at:
https://www.healthaffairs.org/do/10.1377/hblog20200211.544900/full/
● Towse, A., Hoyle, C., Goodall, J., Hirsch, M., Mestre-Ferrandiz, J., Rex J. 2017. Time for a Change in How New Antibiotics
are Reimbursed: Development of an Insurance Framework for Funding New Antibiotics based on a Policy of Risk
Mitigation. Health Policy http://dx.doi.org/10.1016/j.healthpol.2017.07.011
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Toenquire about additional information and analyses,
please contact:
Adrian Towse
Director Emeritus and Senior Research Fellow
Visiting Professor London School of Economics
atowse@ohe.org