Download off-label use - Moodle Lille 2

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Avastin, Lucentis &
Zaltrap, Eylea
Romain Boidin, Julie Trolle, Amirouche Brahimi,
Sonja Nektarijevic, Anne Bodin
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Scandal in the Media!
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Summary

Age related macular degeneration

Avastin and Lucentis

Off-label Use

Two new players : Eylea and Zaltrap

Intravitreal Use of Zaltrap?

What price for Eylea treatment?

Conclusion
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Age related macular
degeneration
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5
4th cause of blindness
Leading cause of
severe vision loss in
industrialized
courtries.
50 million people
worldwide
Proportion of cases of blindness due to each major cause (2008)
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Risk factors & prevalence
Age >50y,
20% of 65-75y
Smoking
High blood
pressure
Heredity
Sunlight
overexposure
Race:
Caucasien
Genetic
Nutrition
Gender:
Femmes
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Clinical symptoms

It first, affected one eye


The blurring of the central vision:

distortion of central vision

blind spots

central scotomas

Loss of contrast sensitivity

Forms alteration

Hallucinations

Blindness
Quality of life:

Difficult to read, difficulty recognising people's faces

Anxiety

Locomotion difficulties, autonomia
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Diagnosis & view measures

Visual acuity test VAC

Eye fundus (dilated eye exam)

Amsler grid

Fluorescein angiogram

Optical coherence tomography OCT
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Macula degeneration, 2 forms
Wet
AMD
20%
Dry
AMD
80%

Dry AMD
 cellular debris
called drusens accumulates
between the retina and the choroid
 Macula light-sensitive cells slowly
deteriorate
 Visual impairment

Wet AMD
 Abnormal blood vessels grow up
from the choroid behind the
retina
 Aggressive and faster progression
 Blindness
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Methods to slow the wAMD disease
progression
Protective factors &
Complements/ Medicines
Ophtalmogy surgery

Laser photo coagulation therapy

Antioxydants, mineral
supplements

Photodynamic therapy
(Verteporfin injections)

HMG Co-A reductase inhibitor
(statin)

Vitrectomy
Medicines : Recombiant monoclonal antibody
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Wet AMD : physiopathology
1- Stress of epithelial tissu
2-
3-
= Angiogenesis Mechanism
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Anti-VEGF : mechanism of action

Intravitreal injection

Receptor mimetism: Catching of VEGF

Inhibition of angiogenesis

Reduction of fluid and exsudats
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Potential targets: VEGF A / PIGF
4 isoforms
VEGF A: more active in angiogenesis
PIGF Placenta Growth
Factor
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Double action of VEGF
Macula
neovascularization
Tumor Angiogenesis:
Colon tumor, ovarian
tumor
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Anti VEGF marketed
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Avastin & Lucentis
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Avastin / Lucentis Mechanism of action
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Lucentis & Avastin
Brand name
Indication
Wet forms of macular degeneration
Macular oedema
Choroidal neovascularisation
Metastatic colorectal cancer; Metastatic
breast cancer; Advanced, metastatic or
recurrent non-small-cell lung cancer;
Advanced or metastatic kidney cancer;
Cancer of the ovary
Molecule
Ranibizumab
Bevacizumab
Half-Life
Plasmatic : 0,5 days
Intravitreal : 3.2 days (calculated)
Plasmatic : 21 days
Intravitreal : 4.9 days
France : 895,57€
USA : 1950$
France : 278 €
USA (March 2013) : 50$
Price
Company
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The development of anti-VEGF
compounds
2002
First results of anti-VEGF therapy
in macular degeneration1
June 2006
FDA approves Lucentis
January 2005
EMA approves Avastin
1993
mAbs targeting VEGF slow
down tumor growth
1989
Genentech first
isolates VEGF
February 2004
FDA approves Avastin
1997
Beginning of the development of Avastin
January 2007
EMA approves Lucentis
June 2005
1st publications showing efficacy of Avastin in
AMD
(1)Preclinical and phase
1A clinical evaluation of
an anti-VEGF pegylated
aptamer (EYE001) for
the treatment
ofexudative AMD.
Eyetech Group study.
Retina. 2002
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Comparative studies
Endpoint
Results
American NIH
multicenter,
single-blind, noninferiority,
randomized
visual acuity after
1 year
Avastin and
Lucentis had
equivalent
effects
IVAN (2012)
UK
multicenter, noninferiority,
randomized
best corrected
distance visual
acuity at 2 years
Lucentis and
Avastin have
similar efficacy
GEFAL (2013)
Programme
Hospitalier de
Recherche
Clinique National
2008
multicenter, noninferiority, double
masked,
randomized
mean change in
visual acuity at 1
year
Avastin was non
inferior to
Lucentis
CATT (2011)
Funding
Methods
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Reconditioning Avastin

Avastin 25mg/mL 16mL : 278€

DMLA : 0.5mg per injection

Risk of infection
 High risk injection to begin with
 Reconditioning increases the risk of introducing germs
 The reconditioning was done by hospitals, pharmacies, or the
practitioners themselves
 In August 2011, the FDA sends out an alert after clusters of Streptococcus
endophthalmitis infections.
 All were linking to the same pharmacy.

The legal frame being progressively built around this practice could improve
the quality and safety of the preparations
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Reconditioning Avastin
Serious adverse events
Is intravitreal Avastin causing more cardiovascular side effects than Lucentis?

Some meta-studies have suggested that intravitreal Avastin may cause
more arterial thrombotic events.

CATT, IVAN and GEFAL :


Did not show any significant difference in side effects between the
treatments

However, none of these studies had the statistical power to detect rare
side effects

These were randomized clinical trials in a controlled environment
Is there a socio-economical effect?

No socialized medicine = disparities in patients
The patients being given Avastin are not from the same socioeconomic
background as the ones receiving Lucentis.
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Is Lucentis overpriced?

Price of a drug ≠ cost of production.

The price rewards innovative research by being set based on the benefit
brought to patients and society.

Was giving such a high price to Lucentis a mistake? Was the size of the target
population underestimated?

The controversy over Lucentis and Avastin illustrates the collision of two
divergent philosophies :

Industrials and governments basing prices on cost/benefit studies

Practitioners and patients who see the possibility of just dividing
Avastin in several injections to be able to afford it
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Off-Label Use
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Off-label Use Background

The marketing authorisation holder has not investigated and tested all
potential applications of the product concerned

The producer of a medicinal product has investigated and tested a certain
application of the product, but nonetheless decides against registering it.

Off-label use may be induced by the government
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Off-label Use European legislation :
definition

Guideline on good pharmacovigilance practices, Annex I : off-label use

Situations where a medicinal product is intentionally used for a medical
purpose not in accordance with the authorised product information.
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Off-label Use European legislation
Pharmaceutical industry liability

Did they knew or should have known of the off-label use?
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How?

Is publicly known (ex : congress)

Takes place on a large scale

Is extensively documented

Accounts for a significant percentage of the medicinal product’s sales
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Was reasonably foreseeable
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Off-label Use European legislation
Pharmaceutical industry liability

Impact of the pharmacovigilance directive 2010/84/CE and regulation
No 1235/2010
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Adverse reaction :


« Ensure that it covers noxious and unintended effects resulting not only
from the authorised use of a medicinal product at normal doses, but
also from medication errors and uses outside the terms of the marketing
authorisation, including the misuse and abuse of the medicinal
product »
Reporting of any use of the medicinal product which is outside the terms
of the marketing authorisation

Member States have to put in place a pharmacovigilance system
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Eudravigilance database (centralised medicines)
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Off-label Use European legislation
Pharmaceutical industry liability

Warn about the risks of off-label use
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Through SmPC and/or package leaflet
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Risk Management plan : post autorisation off-label use (SV.4)

Module XV of EMA’s Guideline on Good pharmacovigilance practices
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Direct healthcare professional communication

Press releases

Messages on the marketing autorisation holder’s website
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Messages disseminated through other internet tools
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Off-label Use European legislation
Ex : Roche liability for Avastin
+ Off-label Use European legislation
Physicians and pharmacists liabilities

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Physicians liability
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Enhanced (article 5, 2001/83/EC)
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Off-label prescribing should better serve the patient’s needs than “onlabel” prescription of an alternative medicine.

Off-label prescribing should have a solid scientific basis.

The prescribing physician should obtain the patient’s explicit consent to
off-label use (informed consent requirement).

The prescribing physician should keep clear, accurate and legible
records of all medicines prescribed, the reasons for prescribing them and
their (side) effects.
Pharmacists liability

Practical application is complicated, a pharmacist often being unaware
that a medicine was prescribed off-label
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Off-label Use European legislation
Physicians and pharmacists liabilities

Examples of Risks in France :
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Disciplinary liability

Civil liability

Penal liability
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Off-label Use European Position for
Avastin/Lucentis
Clinical trials sponsored by healthcare bodies
comparing approved medicines with off-label
medicines was being held in 5 European countries :
The cheaper off-label medicine against the approved
treatment
NICE has included off-label
recommendations
Several sickness funds have entered into
agreements with doctors’ associations
which provide financial incentives to use
off-label medicines
LFSS 2013 and economic RTU
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Off-label Use European Position for
Avastin/Lucentis
EFPIA position paper : Promotion of off-label use of medicines by European
healthcare bodies in indications where authorised medicines are available
November 2011

Decisions on off-label medicine use should remain in the hands of the treating
physician and be taken on the basis of the medical need of the individual
patient
 Medicines may not be promoted for unlicensed uses (Art. 87 of Directive
2001/83/EC).
 Priority to be given to protection of public health over economic
considerations

Promotion of off-label use by healthcare bodies may compromise patient
safety and creates legal uncertainty with regard to product liability

Promotion of off-label use by healthcare bodies sets double standards
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Off-label Use European Position for
Avastin/Lucentis
Decision of the European Court of Justice (Fourth Chamber)
11 April 2013
Activities such as those at issue in the main proceedings, provided that they do not result in a modification of the
medicinal product concerned and are carried out solely on the basis of individual prescriptions calling for processes of
such a kind – a matter which falls to be determined by the referring court –, do not require a marketing authorisation
under Article 3(1) of Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004
laying down Community procedures for the authorisation and supervision of medicinal products for human and
veterinary use and establishing a European Medicines Agency, but remain, in any event, subject to Directive
2001/83/EC of the European Parliament and of the Council of 6 November 2001 on the Community code relating to
medicinal products for human use, as amended by Directive 2010/84/EU of the European Parliament and of the Council
of 15 December 2010.
Do not result in a modification of the medicinal product concerned and are carried out
solely on the basis of individual prescriptions calling for processes of such a kind do not
require a marketing authorisation
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Off-label Use American legislation
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American guidances about unapproved indications for marketed
medicinal products :
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Postmarketing Safety Reporting for Human Drug and Biological Products
Including VaccinesRelated laws
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
Special report situation : unapproved indication
"Off-Label" and Investigational Use Of Marketed Drugs, Biologics, and
Medical Devices - Information Sheet
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Physicians have the responsibility to be well informed about the
product, to base its use on firm scientific rationale and on sound
medical evidence, and to maintain records of the product's use and
effects

Does not require IND
Responding to Unsolicited Requests for Off-Label Information About
Prescription Drugs and Medical Devices
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Off-label Use American legislation
Ex : Roche liability for Avastin
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Off-label Use American Position for
Avastin/Lucentis
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Medicare and Medicaid take charge of both medicines, Avastin and
Lucentis for AMD
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Speeding-up the procedure of authorization of new applications:
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Largely in response to pressures from patient groups eager to have
potentially life-saving drugs available as quickly as possible, FDA has
instituted “accelerated approval,”
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Major limitation: agency cannot act on drugs for which supplemental
applications are not submitted!
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The story
repeat it
self!
Two new players :
Eylea and Zaltrap
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Eylea & Zaltrap approvals
November 2011
FDA approves Eylea for
wet AMD (Regeneron )
November 2012
Eylea has been approved by the EC for
the treatment of patients with wet AMD.
(Bayer Healthcare)
August 2012
the FDA approves Zaltrap (ziv-aflibercept)
February 2013
EC has granted MA in the European
Union for ZALTRAP 25mg/ml (Sanofi &
Regeneron)
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Eylea mechanism of action
EYLEA
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Eylea & Zaltrap
Brand
name
Indication
Neovascular (Wet) Age-Related
Macular Degeneration (AMD)
Macular Edema Following Central
Retinal Vein Occlusion (CRVO)
Indicated for patients with metastatic
colorectal cancer (mCRC) resistant to
or has progressed following an
oxaliplatin-containing regimen
In combination with + 5-fluorouracil,
leucovorin, irinotecan (FOLFIRI)
Molecule
Aflibercept
Ziv-Aflibercept
2 mg (0.05 mL)/ 4 weeks , 8 weeks
Only for intravitreal injection
4 mg/kg as an intravenous infusion
over 1 hour / 2 weeks
France : 810,12 € TTC
France : 313,86 € HT
Dosing
Forms
Price
Company
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Eylea (VEGF trap eye)
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First year: 7 treatment visits, 7 injections of Eylea (2mg /injection)

Second year: frequency of visits and injections depends on anatomical and
visual results of the first year.
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Clinical studies
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VIEW 1 and VIEW 2
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Clinical trials: Phase 3 (pivotal)

Non inferiority study

Study of the Efficacy, Safety of Repeated Doses of Intravitreal VEGF Trap in
Subjects with wet AMD
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The two biggest cohorts of people studied to date in wet AMD
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Including almost 2,500 patients and more than 360 sites worldwide.
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View1 & View2 studies
Studies design
Patient
enrolment
Two Randomized, Double Masked, Active Controlled, multicenter phase 3 studies.
View1: n= 1217, in USA and Canada
View2: n= 1240, in Europe, Asia Pacific, Japan and Latin
America
Patient ages ranged from 49 to 99 years with a mean of 76
years.
Interventions
Endpoints
•
•
•
•
VEGF Trap-Eye dosed 0.5 mg / Every 4 weeks
VEGF Trap-Eye dosed 2 mg / Every 4 weeks
VEGF Trap-Eye dosed 2 mg / Every 8 weeks
Lucentis dosed 0.5 mg / Every 4 weeks
• Primary: prevention of moderate vision loss (loss of >=15
letters) at one year. (week 52 compared to baseline).
• Secondary: best-corrected ETDRS visual acuity at one year
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Mean change in visual acuity
http://performances-medicales.com/ophta/encours/192/03.pdf
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Results of view1 & view2

Treatment with Aflibercept produced equivalent efficacy and safety
outcomes as Lucentis.

Generally favorable safety profile

These studies demonstrate that Aflibercept is an effective treatment for wet
AMD,

Every-2-month regimen offering the potential to reduce the risk from
monthly intravitreal injections and the burden of monthly monitoring.
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Could Zaltrap be used instead of
Eylea?

Is there a real risk to see Zaltrap being used off-label?

There is already a well-known option used off-label in AMD : Avastin

As a second line treatment after Avastin?
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Could Zaltrap be used instead of
Eylea?

Can this use be limited?

Zaltrap's SmPC in Europe :

Osmolarity of Zaltrap : 1000 mOsmol/kg ;


Osmolarity of an eye : 300 mOsmol/kg
Volume to inject to achieve the right dose : 2mg -> 80µL
1 ml/40 mg of aflibercept
1ml/25 mg of aflibercept
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What price for Eylea
treatment?
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AMD Arena in numbers
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



Global net sales: $4,2
billion by 06/2013
Patent expiration in
2016
Top reimbursed drug en
ville in France with:
€390 million in 2012

In Top 5 most successful
new products launches
in biopharma industry
Global net sales 2013:
$1.881 billion
Expected to grab 16%
of the market from
Lucentis



U.S. sales in 2013:
6,254 billion CHF, ($
7,006 billion)
+13% Sales growth VS
2012 at constant
exchange rates
Worldwide net sales
$70 million in 2013
Launches in Eurxope
following approval in
February 2013
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AMD Arena in numbers






Global net sales: $4,2
billion by 06/2013
Patent expiration in
2016
Top reimbursed drug en
ville in France with:
€390 million in 2012

In Top 5 most successful
new products launches
in biopharma industry
Global net sales 2013:
$1.881 billion
Expected to grab 16%
of the market from
Lucentis



U.S. sales in 2013:
6,254 billion CHF, ($
7,006 billion)
+13% Sales growth VS
2012 at constant
exchange rates
Worldwide net sales
$70 million in 2013
Launches in Eurxope
following approval in
February 2013
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AMD Arena in numbers






Global net sales: $4,2
billion by 06/2013
Patent expiration in
2016
Top reimbursed drug en
ville in France with:
€390 million in 2012

In Top 5 most successful
new products launches
in biopharma industry
Global net sales 2013:
$1.881 billion
Expected to grab 16%
of the market from
Lucentis



U.S. sales in 2013:
6,254 billion CHF, ($
7,006 billion)
+13% Sales growth VS
2012 at constant
exchange rates
Worldwide net sales
$70 million in 2013
Launches in Eurxope
following approval in
February 2013
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Reimbursement of Lucentis® in UK
Favorable NICE Recommendation
BUT treatment not to exceed 14 injections
Novartis lowers cost-effectiveness ratio
Additional injections free
Risk-sharing agreement
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Reimbursement of Lucentis® in UK
Favorable NICE Recommendation
BUT treatment not to exceed 14 injections
Novartis lowers cost-effectiveness ratio
Additional injections free
Risk-sharing agreement
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Reimbursement of Lucentis® in UK
Favorable NICE Recommendation
BUT treatment not to exceed 14 injections
Novartis lowers cost-effectiveness ratio
Additional injections free
Risk-sharing agreement
+
57
Reimbursement of Lucentis® in UK
Favorable NICE Recommendation
BUT treatment not to exceed 14 injections
Novartis lowers cost-effectiveness ratio
Additional injections free
Risk-sharing agreement
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Reimbursement of Lucentis® in UK
Favorable NICE Recommendation
BUT treatment not to exceed 14 injections
Novartis lowers cost-effectiveness ratio
Additional injections free
Risk-sharing agreement
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What is a risk-sharing agreement?

Any conditional reimbursement:

Patient access schemes

Value-based pricing

Risk-sharing agreements

Pay-for-outcomes


Performance-based pricing
Coverage with evidence development
Finance based
Price discounts, e.g. in the shape
of:
Outcome based
• Dose cap
• Limited number of
patients
• Free initial stock
• Initial discount
• Return of
treatment/drug cost in
case of failure
• Delayed reimbursement
after proven response
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Risk-sharing Schemes Worldwide
United BioSource Corporation, Coulton L1, Annemans L2, Javier J3, Brown R3, Keskinaslan A4
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Reimbursement of Eylea & Zaltrap
Country
Reimbursment
USA
Australia
Japan
Switwerland
Yes
Germany
UK
France
USA
France
Rest of UE
Yes
Pending
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Pricing Eylea

Eylea It is very expensive. A typical fill can cost $1,972 or more for 1 kit of
2mg/0.05ml Eylea.

Eylea demonstrating efficacy on a par with Lucentis, but needing to be
dosed less frequently (half as often; on paper at least)

Eylea has not only assumed market share at the expense of Lucentis, but also
off-label Avastin, which is available at a significantly cheaper cost of around
$50 per injection (some 37-times cheaper than Eylea)

Eylea & Lucentis : The manufacturer has agreed a patient access scheme
with the Department of Health which involves a confidential discount applied
to the list price of aflibercept solution for injection. The level of the discount
is commercial in confidence.
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Pricing Eylea
Point of view of the Health Care
Provider
Point of view of the manufacturer

Marginal costs of manufacturing

Drug acquisition costs

Research & Development

Administration costs

Marketing

Monitoring costs

Meeting regulatory requirements

Managing adverse events
+
Costs
associated with
blindness

Low-vision aids

Rehabilitation

Residential care

District nursing

Community care

Cost of treating complications like
depression and falls /hip replacement
In total
=£6067 in the first
year and
= £5936 in
subsequent years
When treated with Lucentis
= £8000 saving over a
10 year period
* study of blindness in the UK that focused on people with age-related macular degeneration (Meads and Hyde 2003)
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Pricing Eylea
Tretment
Administration and
monitoring
£257,45 per visit
Price per
dose
Fluorescein angiogrphie
= £117
+
=
+
+
Assistance per
visit
= £90
+
+
+
No cost of
adverse effects
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66
First year of treatment: one-stop model
Month
Month
1
1
2
2
3
3
4
4
5
£816 per dose
6
7
8
£761,20 per dose
8
9
10
10
12
6
7
9
11
5
11
= £13 510
£8 352 =
12
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67
Total treatment prices
for 1 year treatment
£ 13 510 ($22,660)
£8 352 ($14,018)
Of which £9,000 Eylea
Of which £18,300 Lucentis
DISCOUNT
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Pricing in France

Lucentis


ASMR II
Eylea

ASMR V
« Si c’est pas mieux c’est moins cher, si c’est mieux c’est peut être
plus cher »
Mr Teisseire
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69
Conclusion

Innovation is still in march, new products with new targets are in the pipeline.
A new drug is going to be associated with Eylea. What price to give it?

Should we give priority to cost over Health?

What role for the governments in cost-effectiveness related decisions?

What role should patients have in the decisions?

This episode constitutes a precedent of off-label use of a very similar
compound for economic reasons.
+
Any
questions?
Thank you for your
attention
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71
Sources

www.cehjournal.org/article/changing-patterns-in-globalblindness-1988-2008/

Nature

NICE guidance

WHO website

Sante.gov, ameli.fr

FDA website, EMA website

EFPIA website

European comission

HAS website

Bayer website

AMD ressource center