Does the potential for drug resistance mean

that new antibiotics should be evaluated

differently from other medicines?

Abigail Colson

12 July, 2017

Co-authors: Alec Morton, Anna Trett, Axel Leporowski, Ramanan Laxminarayan, and others from DRIVE-AB WP1C

DRIVE-AB

Developing new economic models to incentivise

antibiotic discovery and development activities

while safeguarding the efficacy of antibiotics by

researching and advocating their appropriate

use.

October 2014 – September 2017

DRIVE-AB Work Packages

• WP 1A: Define “responsible” use of antibiotics

• WP 1B: Set, communicate and revise public

health priorities

• WP 1C: Develop antibiotic valuation models

• WP 2: Create, test and validate new economic

models

• WP 3A: Coordinate and manage the project

• WP 3B: Stakeholder platform and external

communication

WP1C Papers

• AMR and prophylaxis

• Future resistance

rates with structured

expert judgment

• Option value of a

novel antibiotic (panflu

example)

• HTA review and

recommendations

HTA is conducted according to set

guidelines.

HTA is conducted according to set

guidelines.

There’s no guidelines or methods

advice specific to antibiotics.

Antibiotics are treated like any other drug.

Antibiotics are different from other drugs.

• Transmission benefit: Treating

one patient decreases overall

incidence.

• Resistance cost: Using an

antibiotic selects for resistance.

Antibiotic resistant bacteria © Microrao, CC-BY-SA 4.0

Antibiotics are different from other drugs.

• Diversity benefit: Having multiple antibiotics may reduce selection pressure and delay resistance.

• Enabling benefit: Many surgical and medical procedures rely on prophylaxis with antibiotics.

• Insurance/option value benefit: We may want to have an antibiotic in reserve before we really need it, so it’s ready if resistance arises or worsens.

Cesarian the moment of birth © Diliff, Free Art License

Antibiotics are different from other drugs.

𝐼𝐶𝐸𝑅𝐴𝐵𝑋 =𝐶 − 𝑆 − 𝑆𝑡 − 𝑆𝑑𝑉 + 𝑉𝑡 +𝑉𝑑

𝐼𝐶𝐸𝑅 =𝐶 − 𝑆

𝑉

• C – Direct cost of the new technology

• S – Direct savings from the new technology

• V – Direct health benefits from the new technology

• St – Savings from the new technology through avoided transmission

• Vt – Health benefits from the new technology through avoided transmission

• Sd – Savings from the new technology through protective effect on existing portfolio of antibiotics

• Vd – Health benefits from the new technology through protective effect on existing portfolio of antibiotics

We searched HTA reports from the past 10

years in 11 countries.

Country Agency Full Name

France HAS French National Authority for Health/Haute Autorité de Santé

Germany IQWiG Institute for Quality and Efficiency in Healthcare/Institut für Qualität und

Wirtschaftlichkeit im Gesundheitswesen (GBA and DIMDI also searched)

The Netherlands ZI National Health Care Institute/Zorginstituut Nederland

Norway NOKC Norwegian Knowledge Center for the Health Services

Scotland SMC Scottish Medicines Consortium

Spain AETS National Health Technologies Assessment Agency/Agencia de Evaluación de

Tecnologías Sanitarias

UK NICE National Institute for Health and Clinical Excellence

Wales AWMSG All Wales Medicines Strategy Group

We included the 10 largest EU economies + Norway.

Austria, Belgium, Italy, Poland, and Sweden do not have HTA reports on antibiotics.

We selected 5 antibiotics for review, based on the number of available reports.

Example: Fidaxomycin

• Transmission benefit

– This [medicine] significantly reduces the risk of infection for other people in the vicinity of the patients, but also the risk of reinfection for the patients themselves. [GBA]

• Diversity benefit

– CHMP [Committee for Medicinal Products for Human Use] also noted that fidaxomicin belongs to a novel antibiotic class, which it considered important from an antibiotic resistance perspective, as it limits the risks for cross-resistance. (p. 5) [AWMG]

Current situation

• Awareness exists among HTA assessors

– Differing levels of awareness across countries

– Differing levels of awareness within countries

• BUT discussions are qualitative

Current situation

• Awareness exists among HTA assessors

– Differing levels of awareness across countries

– Differing levels of awareness within countries

• BUT discussions are qualitative

Is quantification possible?

This is a work in progress. Results are indicative to show logic.

Carbapenem-resistant Acinetobacter baumannii– Important cause of healthcare associated infections

– High morbidity

– High mortality (20%)

– Low prevalence

Rex and Spellberg (2013) conduct a CEA of a hypothetical

CRAB monotherapy, focused on direct costs.

A worked example: CRAB

Spellberg, Brad, and John H. Rex. "The value of single-pathogen antibacterial agents." Nature Reviews Drug Discovery 12.12 (2013): 963-963.

43,200 CRAB patients

8,640 patients died

34,560 patients treated

successfully

25,920 CRAB patients treated

with new monotherapy

25,920 patients treated

Costs = 25,920 x 25,000

Savings = 25,920 x 13,671

Total costs= (25,920 x 25,000)-(25,920 x 13,671)

€293,647,680

17,280 patients who would have had CRAB

Total costs averted from preventing CRAB infections

17,280 x 13,671

€236,234,880

Year 2 reduction in transmission → 40% lower new incidence (Doan et al 2012)

Direct costs: From directly treating CRAB infections with new monotherapy

Mortality rate: 20%

Cost of treating resistant case : €13,671Cost of new therapy: €25,000

Transmission costs averted: From avoided onward transmission of CRAB

Year 1

Estimating direct & transmission costs

43,200 CRAB patients

8,640 patients died

34,560 patients treated

successfully

25,920 CRAB patients treated

with new monotherapy

12,400 QALYs

17,280 patients who would have had CRAB

82,900 QALYs

Year 2 reduction in transmission → 40% lower new incidence (Doan et al 2012)

Direct benefits: From directly treating CRAB infections with new monotherapy

Mortality rate: 20%

Risk reduction of 50% with new monotherapy

Transmission benefits: From avoided onward transmission of CRAB

Year 1

Estimating direct & transmission benefits

All ICU patientsN= 1,910,975

Cost saved:7% cost reduction with introduction of CRAB monotherapySource: expert elicitation

QALYs saved:3.5% mortality reduction with introduction of mono-therapySource: expert elicitation

Costs savedICU populationX Carbapenem prescription rateX Resistance rate of CarbapenemsX Cost of resistant infection X 7% reduction

2.5% (prescription rate of carbapenems) x40% (resistance rate)Source: ECDC point prevalence survey

QALYs savedICU populationX Carbapenem prescription rateX Resistance rate of carbapenemsX Mortality rate of ICU infectionsX Life years gainedX Life quality of years gainedX 3.5% reduction

1,910,975x 2.5% = 47,774X 40% = 19,110X 20% = 3,822X 8 = 30,576

X 0.6 = 18,345X 3.5% =

642 QALYs

1,910,975x 2.5% = 47,774X 40% = 19,110

X 13,671 = 261,249,392X 7% =

€18,287,458

Estimating diversity benefits

Least optimal

-10000 -8000 -6000 -4000 -2000 0 2000 4000 6000 8000 10000

Diversity benefit

Transmission benefit

Direct benefit

Cost/QALY (€)

High Low

Most optimal

In this example, uncertainty surrounding

direct benefits outweighs other parameters

Recommendations

1. Assessment should, as appropriate, include a sensitivity analysis of

the impact of resistance to the new antibiotic, both initially and over time.

– If including resistance, ICER is a discounted stream of benefits.

– Expert elicitation is an option for predicting future resistance rates.

2. Analysis should take place at the population level.

3. Analysis should take place within the context of clinical guidelines on

the recommended treatment for the indication in question.

Recommendations

4. In addition to the direct costs and benefits associated with treating one

patient with the antibiotic, where relevant, the transmission and diversity

benefits should also be taken into account.

- These won’t be relevant for all products.

- They could vary a lot, depending on the characteristics of the drug/infection.

5. Decisions about whether to approve an antibiotic for treatment should

be made independently of the decision to approve the antibiotic for

prophylaxis.

• Antibiotic resistance is a complex issue

• But principles of public health planning still apply

– What is the need?

– Do the benefits exceed the costs?

• Current work represents a start in thinking about

– Defensible techniques for modelling

– Reasonable processes for making decisions

Conclusions

THANK YOU!

abigail.colson@strath.ac.uk

This research has received support from the Innovative Medicines Initiative Joint Undertaking under

grant agreement n°115618 [Driving re-investment in R&D and responsible antibiotic use – DRIVE-

AB – www.drive-ab.eu], resources of which are composed of financial contribution from the

European Union’s Seventh Framework Programme (FP7/2007-2013) and EFPIA companies’ in kind

contribution.