Download 2011 - Moodle Lille 2

Master 2 - Réglementation du
Médicaments dans
l’Union Européenne
252012-2013
Février 2013
Méthodes
d'évaluation de
l'innovation des
médicaments en
Europe
Louise BILLON
Virginie BLANC
Mehdi CHERBATLI
Anne GOURION
Laure TRAUCHESSEC
Cas de la France, du
Royaume-Uni, et de
l’Allemagne
1
AGENDA
• Introduction
• Agencies presentation and comparison
• Assessment Examples
• Perspectives
2
INTRODUCTION
3
Innovation & medicines
Truly innovative:
• offers additional clinical efficacy
and/or effectiveness as
compared to current care
• potential to lead to key
improvements in health
outcomes at the individual and
the population levels
4
Source : A call to make valuable innovative medicines accessible in the European Union – OMS – July 2010
Innovation in Medicines
 Assessment particularities
• Distinction between the data needed :
• to obtain a MA
• to get an innovativeness and value appraisal
• Criteria for MA
• Quality
• Safety
• Efficacity
• Criteria for pricing and reimbursement decision
•
•
•
•
Therapeutical need
Relative effectiveness
Value for health
…
Source : A call to make valuable innovative medicines accessible in the European Union – OMS – July 2010
5
Healthcare Systems in Europe
• Vary very widely
• Conventionally classified into :
• Beveridgian systems ⟺ national health systems
• Based upon the funding of the resources spent on health through
taxation
• As in the United Kingdom,
• Bismarckian systems ⟺ health insurance systems
•
•
•
•
Professional affiliation compulsory
Funding by employer and employee contributions
Based on the principle of solidarity
As in France or in Germany, although increasingly these latter do
also draw part of their financing from taxation.
6
Overview (2010)
FRANCE
• Population : 65,5 million
• GDP/inhabitant : 27 550 €
UNITED KINGDOM
• Population : 63,2 million
• GDP/inhabitant : 27 870 €
GERMANY
• Population : 81,8 million
• GDP/inhabitant : 31 320 €
Source : WHO Global Health Expenditure atlas-World Health Organization 2012
7
Overview
8
Source : WHO Global Health Expenditure atlas-World Health Organization 2012
Healthcare expenditure
• Part of GDP alloted to health expenditure in 2009
9
Source : OCDE, 2009
Healthcare expenditure
 % of GDP
2007
2008
2009
2010
FRANCE
11,1
11,2
11,9
11,9
UNITED
KINGDOM
8,4
8,9
9,8
9,6
GERMANY
10,5
10,7
11,7
11,6
Evolution
10
AGENCIES
11
Health Technology Assessment
Agencies
FRANCE
UNITED
KINGDOM
GERMANY
12
AGENCIES
France
13
Medicines expenditure in France
• Bismarkian model of Health System
• Health expenditure for drugs in 2011 = 25.7 billion €
• 76% in private sector
• 24% in public sector
• = 1.9% of GDP
• Medicines expenditure increased in the last decade
• Important pressure on regulation
14
 Medicines expenditure now regulated
 ONDAM respected in 2011
Rapport d’activité du CEPS 2011
Process for private sector
Marketing Authorisation
HAS – Commission de la transparence
SMR, ASMR,
Targeted population
UNCAM
CEPS
Reimbursement
Price
15
Ministry decision
OJ publication
Source: Rapport d'activité 2011 du CEPS
Process for hospital
Marketing Authorisation
HAS – Commission de la transparence
SMR, ASMR,
Targeted population
Ministry decision – OJ publication
Health Trust
Approved
Drugs included
in GHS
Hospital
Drugs excluded
of GHS
Retrocession
CEPS
Price
Call for bids
Ministry decision - OJ publication
16
Haute Autorité de Santé &
Commission de la Transparence
HAS
• Independent Public Health authority
• Financed by subventions (91%) and own revenue (7%)
• ≠ Missions
 Provide opinion to public decisionary instances for collective final
endorsement of cares
CT
•
•
•
•
One of the 8 commissions of the HAS
20 voters : all scientists + 6 deputy members
8 consultative members: ministries, health insurance, ANSM, LEEM
Missions : assessment of drugs / opinion / information
17
CT Opinion
 Content
 SMR  Favorable /unfavorable for reimbursement
• For all the indication covered by the MA? or restricted indication?
 ASMR  Assessment of the progress
• What is the progress ? For which population?
 Targeted population
• Quantitative estimation
 Recommendation
• Place of the drug in therapeutic strategy
• Terms of use
 Uncertainties
• Need of complementary studies?
Only opinion
• Decision by CEPS, UNCAM and Ministry
• Not actionable
18
CT Opinion
 Medical Benefit : SMR
Criteria
• Efficacy
• Safety (adverse reactions)
• Seriousness of the disease
• Preventive/curative/symptomatic characteristic
• Role in the therapeutical strategy
• Impact on Public Health
SMR levels
• Important/Major
• Moderate
• Low
• Insufficient
19
CT Opinion
 Improvement in Medical Benefit : ASMR
Criteria
Comparison with existing/reference care
Comparative care must be choosen carefully
Pivotal study may not be sufficient
 Additional study may be required
ASMR levels
I = major
II = important
III = moderate
IV = low
V = no improvement
20
CT Activities
• 250 first registration assessments per year
• 20-40 new indication assessments per year
ASMR ≤ 4 for 1st registration
ASMR ≤ 4 for new indication
30
30
25
25
ASMR
20
ASMR
20
IV
III
15
IV
III
15
II
I
10
5
II
I
10
21
5
0
0
2007
2008
2009
2010
2011
2007
2008
2009
2010
2011
Pricing
CEPS
= Interministerial committee, under the authority of ministeries in
charge of Health, Social Security and Economy
• Composition
• 1 president + 1 vice-president for drugs
• 26 members from DGS, DGSS, DGCCRF, DGOS, Health Insurance
representing members
• Consultative members from Ministries concerned (budget, research,
agriculture…) depending on the subject
• Mission: price fixing
• Drugs
• Medical Devices
22
Pricing
• Principle :
• Following CT opinion
• Convention between industry and CEPS = « accord cadre » Leem/CEPS
• New dispositions since December 5th 2012
• For new drugs
• For innovative drugs
• Criteria:
•
•
•
•
•
•
ASMR level
Price of similar treatments
Sales volume expected/observed
Terms of use expected/observed
Prices in other EU countries
Medico-economic assessment results
23
Pricing : exceptions
Sometimes CEPS does not follow CT opinion
= CEPS decision based on different criteria than CT
 ASMR granted despite CT opinion
• Medical need not fully covered by other treatment
• Responder/non responder = no statistical difference vs
comparator but active, ASMR V for CT, but special interest for
some patients
 ASMR recognized by CEPS
• Old comparator with low cost (price incompatible with new prices
of products)
 ASMR recognized by CEPS
24
UNCAM assessment
• UNCAM :
= Authority grouping the 3 main health insurance systems
• Reimbursement rate offered based on HAS/CT opinion
SMR
Important/Major
Reimbursment rate
65% or 100%*
Moderate
30%
Low
15%
Insufficient
negative opinion
* according to seriousness of the disease.
25
Conclusion
• Key actors: HAS/CT, CEPS
• Assessment based on SMR/ASMR
• No economic consideration for market access
• France give the same chances to every patient for access to
treatments
• Cost for the Social Security
• Supposedly transparent
• no clear algorithm between ASMR and prices
• Possible rebates negociations
26
Future :
 Medico-economic assessment ?
• CEESP
• Created in July 2008
• Composition : 31 members, with competences in Economic Assessment
and Public Health
• Missions
• until 2012 : possibility of recommendations and opinions in order to gain
a more efficient use of the products
• with LFSS 2012 : medico-economic assessment required which will be
used for price negociation (decree of October 2012)
• When?
• if industrial asks for ASMR I, II, III and the product may have a significant
impact on Health Insurance expenses
• How?
• File deposit : when filed to the CT
• Content of the file: CT file + medico-economic data
27
Future :
 Medico-economic assessment ?
• ITR: Index Thérapeutique Relatif
• Replacement of SMR and ASMR
• Criteria for assessment of new drugs
• Primary criteria : efficacy vs comparative drug
• Secondary factors : safety and conditions of use
• Objective : determination of price and reimbursement
• ITR levels:
• Inferior  no reimbursement
• Comparable  reimbursement but lower price
• Superior  reimbursement with higher price
• Minimal
• Moderate
• Major
28
AGENCIES
United-Kingdom
29
Healthcare System in the UK
• Beveridgian model
• Medicines prescriptions
• Prescription charge (England: £7.65 per item from 01-Apr-2012)
• contribution to the NHS
• not related to the cost of the medicine
• But free prescription for a large proportion of the
population
• children (under 16)
• the elderly (over 60)
30
Healthcare System in the UK
• Unpalatable fact that the resources available for the
provision of healthcare are finite :
“No publicly funded healthcare system, including the
NHS, can possibly pay for every new medical treatment
which becomes available. It makes sense to focus on
treatments that improve the quality and/or length of
someone's life and, at the same time, are an effective
use of NHS resources.”
31
Healthcare System in the UK
The NHS in England : current structure
32
Source : www.abpi.org.uk
Healthcare System in the UK
• Key Facts on the costs of medicines
0,9%
of GDP on
medicines
Proportion of the
NHS budget spent
on medicines :
 10% in 2011
New medicines
 only 10% of the
NHS’s total expenditure
on medicines
Source : www.abpi.org.uk
The NHS spent
about £12
billion on
medicines in
2009
Branded medicines
 ≈ 80% of the
NHS drug bill
33
Pricing in the UK
• Controlled under the Pharmaceutical Price Regulation
Scheme (PPRS)
• voluntary, non-statutory scheme
• regulates the profits that companies can make
• renegotiated periodically by the Department of Health and the
ABPI ( 2009  2014)
• seeks to achieve a balance between :
• reasonable prices for the NHS
• and a fair return for the industry to enable it to research, develop
and market new and improved medicines
• New products introduced following the granting of MA
• priced “at the discretion of the company”
34
Reimbursement
• HTA in the UK  NICE
• = National Institute for Health and ClinicalExcellence
• Special Health Authority funded by the Department of Health
• Set up in 1999 to reduce variation in the availability and quality of
NHS treatments and care
• Composition
• 1 chairman
• 8-10 members who are not officers of the Institute
• 6 members who are officers of the Institute
• Chief Officer, Chief Finance Officer, Director of Clinical and Public Health,
Director of Health Improvement
35
Reimbursement
 NICE
• Functions
• balance between benefits and costs
• the degree of need of persons for health services
• the desirability of promoting innovation in the provision of
health services
• Provides guidance to the NHS to help resolve uncertainty
about
• which medicines, treatments, procedures and devices represent
the best quality care
• and which offer the best value for the money allocated to the
NHS
36
Reimbursement
 Evaluating new treatments
• Technology Appraisal Systems - Criteria
• Is the technology likely to result in a significant health benefit […]
if given to all patients for whom it is indicated?
• Is the technology likely to result in a significant impact on other
health related government policies ?
• Is the technology likely to have a significant impact on NHS
resources if given to all patients for whom it is indicated?
• Is there likely to be significant controversy over the interpretation
or significance of the available evidence on clinical and cost
effectiveness?
37
Reimbursement
 Multiple & Single Technology Appraisal
• MTA is for a disease area or class of drugs and contains either
• new evidence gathered after the launch of a drug or
• new economic modelling.
• STA has been developed to provide early guidance for
• new drugs targeting a single indication or
• new indications for drugs already on the market.
38
Reimbursement
 QALY
• Quality-Adjusted Life Year ⟺ measuring effectiveness
and cost-effectiveness
• How is this calculated ?
• Gives an idea of how many
more life years of a reasonable
quality a person might gain as
a result of treatment.
• Adjusted to patient’s quality of
life (between 0 and 1).
39
Reimbursement
 QALY
40
Reimbursement
 ICER
• Superiority
• ‘incremental cost effectiveness ratio’ (ICER) : decide whether the
increased cost gives value-for-money in terms of improved health.
• express ICERs in terms of cost/QALY
• ICER ‘threshold’ above which a technology would invariably be
deemed cost ineffective (around £25,000)
• Particular circumstances : ICERs above the range of £50 000/QALY
may be considered as cost effective.
41
Reimbursement
 Example
• Patient X has a serious, life-threatening condition :
Patient X
Standard
treatment
New drug
Additional lifetime
1 year
1.25 year
Quality of life
0.4
0.6
QALY
0.4
0.75
Cost
£3,000
£10,000
 The difference in treatment costs (£7,000) / QALYs gained (0.35)
= £20,000/QALY.
• The new treatment would cost £20,000 per QALY.
42
Reimbursement
 NICE decisions
• NICE health technology appraisal decisions :
1. Recommended :
2. Restricted :
To be made available to all
patients considered within the
scope of the appraisal
To be made available to a subgroup of patients relative to
the scope of the appraisal
3. Not recommended :
4. Terminated :
Not recommended for use by
any patient relative to scope
Appraisal not complete and
decision not reached
43
Reimbursement
 NICE decisions
Not recommended
decisions

44
Source : Office of Health Economics (OHE)
Exceptions
• Patient Access Scheme (PAS)
• created by drug companies
• In which they offer discounts or rebates to the NHS
•  enables patients to have access to high cost drugs
•  “PAS list” published by the NICE to recommend treatments
which have been deemed too expensive and not cost effective
• Cancer Research Funds
• Spans 2011-2014
• Mostly government-funded (£200 million/year)
• Conditions for applying :
• Living in England (depending on the SHA)
• Only through oncologist
• Must have considered all the other options
45
Reimbursement
 NICE & ICER - Controversy
• ICER is controversial because of its utilitarian approach to
determine who will or will not receive treatment.
• Efficiency takes priority over equity : rejection of
treatments which could improve and save lives
• Difficulty in evaluating objectively quality of life and costs
(especially indirect ones) and defining a threshold
• Health care resources are inevitably limited, and need to be
allocated in a way that is approximately optimal for society
46
Undergoing reforms
• The Health and Social Care Act in 2012
• Abolishment NHS primary care trusts and Strategic Health
Authorities (SHAs),
• Becoming “clinical commissioning groups” partly run by
the general practitioners, thus empowering them
• What would it change for the NICE ?
• NICE  National Institute for Health and Care Excellence
• Implementation of the Value Based Pricing (VBP) instead
of Pharmaceutical Price Regulation Scheme in 2014
47
AGENCIES
Germany
48
Healthcare system
• Bismarckian model :
• Professional affiliation compulsory
• Funding by employer and employee contributions
• Based on the principle of solidarity
• More than 250 different insurance funds
• Private and public
• Autonomy of each insurance fund :
- Provides for freely contribution rates
- Important role of negotiations with representatives of doctors and hospitals
• Patients are free to choose their insurance fund
Insurance funds are excedentary
13.8 billion in 2012
49
Healthcare system
• Coexistence of public and private healthcare insurances
• Choose their health insurance fund
Insured person
< 49 500€
> 49 500€
Free choice
SHI
• Public
• Compulsory for all workers
with gross revenue < 49
500€/year
• 90% of the German
population
Private
• Optional
• 10% of the German
population
• More complete coverage
50
Healthcare System
• Key Facts on the costs of medicines :
60% of
generics
(price)
Health
expenditure:
2721€/inhabitant
in 2009
Medecines
expenditure :
1,8% of GDP
in 2009
GKV spent 32
billion € for
medicines in
2010
Medecines
expenditure :
15% of health
budget in 2009
Source : OCDE, Panorama de la Santé 2011, op. cit & IMS HEALTH, Midas, Market segmentation, June 2009
51
Agencies Organisation
Federal ministry of Health
G-BA
Specific request
Appraisal of evidence
regarding
Assessment of best
available evidence on
safety and effectiveness
needs and costs
Directive
IQWiG
Recommendation
Evidence report
52
G-BA Gemeinsame Bundesausschuss
• Federal Joint Committee created in 2004
• Composition :
• 13 members :
• 3 impartial members including the chairman
• 5 representatives of the Sickness fund
• 5 representatives of health care providers :
Vote
Physicians, dentists, psychotherapists and hospitals
• 5 patients’ representatives : can file application
 Cannot vote
53
G-BA
• Missions :
• Responsible for reimbursement decisions in the GKV
• Based on IQWiG opinion
• Issues standardized and binding directives in order to translate
the legal framework into practice
• directives are legally binding
• is called “little legislator”
54
IQWiG
• Independent scientific institut created in 2004
• Missions
• Commissionned by G-BA or the federal Ministry of Health
• Treats Issues of fundamental importance on its own initiative
• Composition :
• 12 members : 6 representants of health insurances
6 representants of healthcare providers
• Finance :
• by contributions from the members of all statutory health
insurance funds (GKV)
• The amount of levy is fixed by G-BA each year
55
IQWiG
• Responsibilities and objectives :
• Objectively reviews the advantages and disadvantages of health
care services for patients.
• Production independent and evidence-based reports on :
•
•
•
•
Drugs
Non-drug interventions (surgical procedures….)
Diagnostic and screening test
Clinical practice guidelines (CPGs) and disease management
programs (DMPs)
• Providing easily understandable health information for the
public.
56
IQWiG
• Basic principles :
• Independence :
• Scientific work carried out in an independent manner
• Notifiable conflict of interest
• Objective and scientific evidence-based
• Patient oriented :
• IQWiG uses criteria that are important to patients.
• Transparent :
• Publication of all results (final & preliminary reports, dossier assessment,
working paper etc.) acessible to all
• Scientists, industry, professional societies, doctors, and patients have the
opportunity to submit comments on IQWiG's work at different stages in the
project.
57
IQWiG
• Method :
• Systematic search in the international scientific literature
• Produces a synthesized benefit analysis from these results
• Produces report have been commissioned by the G-BA
 Contain recommendation for the G-BA
NB : IQWiG does not make the decision as to
whether the costs of a service should be
reimbursed by the health insurance funds.
Only the G-BA makes this decision.
58
2011 : Pricing and
reimbursement reform
• Before 2011 : Manufacturers are free to set prices of all drugs
• Prescription drugs automatically reimbursed once market approval
unless they are included in the negative list
• No formal economic evaluation
• 2011 : AMNOG (Act for the restructuring of the pharmaceutical
market in statutory health insurance)
• Benefit assessment for every new drug
• New onus of proof on manufacturer to demonstrate added benefit vs
an appropriate comparator
• Price negociation
59
Organisation of Medicine's Assessment
Market entry
Month 3
Submission of a dossier by
the manufacturer
Benefit Assessment
( IQWiG )
Month 6
Decision about additional
benefit G-BA (appraisal)
Additional benefit ?
Month 12
Price negociation
(manufacturers, Statuary
health insurance)
60
Drug assessment
• Early benefit assessment
• For new registered medicinal products
• Requested by G-BA : Choose of comparator, population, …
• Based on a dossier prepared by the manufacturer
• In the first year
• IQWIG evaluation
• 5 levels of added benefit :
•
•
•
•
•
•
Major
Considerable
Minor
Unquantifiable added benefit
No added benefit
Less benefit
• Only opinion
• G-BA decision
61
Drug assessment
• Added benefit criteria
• Approach developped by the IQWIG : evaluation of the extent of added
benefit
Outcome Category
Survival time
(Mortality)
Symptoms (Morbidity)
Quality of life
Adverse effects
Major
increase
Long terme freedom from
serious or severe
symptoms or complication
Major
improvement
Extensive avoidance of
serious or severe
adverse effect
Modarate
increase
Alleviation of serious or
severe symptoms or
complication
Non serious symptoms or
complication : Significant
reduction
Significant
improvement
Serious or severe
adverse effect :
Relevant avoidance
Other advers effects :
Significant avoidance
Any
increase
Serious or severe adverse
effect : Any reduction
Non serious symptoms or
complication : Reduction
Relevant
improvement
Serious or severe
adverse effect : Any
reduction
Other advers effects :
Relevant avoidance
Major
Sustained great improvement in therapyrelevant benefit whici has not previously
been achieved vs appropriate comparator)
Added benefit
Considerable
Marked improvement in therapy-relevant
benefit whici has not previously been
achieved vs appropriate comparator)
Minor
Moderate and not only marginal
improvement in therapy-relevant benefit
whici has not previously been achieved vs
appropriate comparator)
62
Pricing
Proof of added benefit
The price will be in proportion of the
added benefit
No price negociation
Reference pricing
Lower price if less benefit
63
Pricing
Decision about additional
benefit (G-BA appraisal)
no
Additional benefit ?
yes
Referent
price
yes
Reference price
applicable ?
Price negociations
SHI/manufacturer
<
no
If requested by
manufacturer, health
economic evaluation
Price similar to
comparator
Agreement ?
no
yes Reimbursable
price
Decision of
arbitrage board
If requested by SHI or manufacturer,
health economic evaluation
• Negociation between SHI and G-BA
64
Conclusion
• Germany is an important market for the industries :
• First pharmaceutical market in Europe
• Price given in Germany is usually used as a reference in many European countries
• AMNOG :
• Benefit assessment
• Hopefully saving 1.7 billion €/year after the last reform
• Mandatory rebates granted by pharmaceutical manufacturer in
2011 : 749 million €.
Consequence :
Some manufacturers have resorted to not putting their drugs
on the German market
Less access to innovation ?
65
COMPARISON
66
Comparison
France
UK
Germany
Since …
-
Price
Reimbursement
- 1994
- 1999
- 1954
- 1999
- 2011
- 2005
HTA
HAS/CT
NHS/NICE
G-BA/IQWiG
Time of
assessment
Before launch
Before launch
After launch or on
request
Reimbursement
Positive list
Negative list
Negative list
Reimbursement
criteria
SMR
ICER
Added benefit
level
% of
Reimbursement
Different levels
depending on
SMR
Yes/No
Yes/No
Maximum price
67
Comparison
France
UK
Germany
Pricing
Negociation/
declaration with
CEPS
Taken as set by
manufacturer
Free for one year
then negociated
with G-BA
Pricing criteria
ASMR and
« Accord cadre »
N/A
Added benefit
Final
reimbursement
decisions
Health Minister
NHS – Department G-BA
Of Health
68
ASSESSMENT EXAMPLES
69
ASSESSMENT EXAMPLES
Zytiga®
70
Metastatic Prostate cancer
Not to confuse :
• Adenocarcinoma prostatic :
 • 1st male cancer
 • 2nd cause of death by
cancer ( 9000 †/year in France)
Evolution :
• Slow (15 years)
• Hormonoresistance
• Benign prostate hyperplasia :
 85% of men > 50 years
71
Source : Han et Al. J Urol 2003
Metastatic Prostate cancer
 Treatment strategy
72
Source : www.oncologik.fr
®
Zytiga
 Abiraterone acetate
• Pharmacological class : antineoplastic, antiandrogen
• Mechanism of action :
• Converted in vivo in abiraterone
• Inhibitor of androgen biosynthesis
• Therapeutic Indication :
In association with prednisone or prednisolone in metastatic castration resistant
prostate cancer in adult men :
• who are asymptomatic or mildly symptomatic after failure of androgen
deprivation therapy in whom chemotherapy is not yet clinically indicated
• whose disease has progressed on or after a docetaxel-based chemotherapy
regimen.
• Pharmaceutical Company :
Source : www.ema.com
73
®
Zytiga
 Assessment story
06/2012
05/2012
03/2012
02/2012
France
UK
Germany
UK
09/2011
MA (UE)
74
COU-AA-301 – Phase III study
• Study COU-AA-301 design
• Randomised, Double-blind, Placebo-controlled
• Comparing efficacity and safety of 1 regimen of abiraterone plus prednisone versus placebo
plus prednisone
• In previously treated men with metastatic castration-resistant cancer progressing after
docetaxel
• Objectives :
• Primary objective : demonstrate superiority on survival
• Others: evaluation of safety, further characterisation of PK and assessment of the potential
utility of circulating tumour cells (CTCs) as a surrogate for clinical benefit .
• Endpoints
• Primary endpoint  overall survival
• Secondary endpoints : PSA response rate; Time to PSA progression; Radiographic progression
free survival
• Treatment
•
1195 patients, randomised in a 2:1 ratio)
• ❶ Abiraterone arm  prednisone 5 mg twice daily + abiraterone 1000 mg once daily
• ❷ Placebo arm  prednisone 5 mg twice daily + placebo once daily
75
COU-AA-301 – Phase III study
• Overall survival : interim analysis
Median overall survival :
Abiraterone : 14.8 months
Placebo : 10.9 months
Reduction in risk of death:
35.4% vs placebo
(HR=0.65, p<0,001)
• Results
• Superiority over placebo in intermediary analysis
•
Independent Data Monitoring Committee recommended unblinding and cross-over of patients
receiving placebo.
• MA granted
Source : De Bono et al. N Engl J 2011;364: 1995-2005.
76
HAS/CT Assessment: Key conclusions
Study considered
Pivotal studies COU-AA-301
SMR important
• Prostate cancer is a life-threatening disease
• Curative and 2nd line treatment treatment
• Efficacy/ADR ratio important
• Therapeutical alternative exists
• Public Health interest : low
ASMR III
 ASMR : moderate based on efficacy and tolerance
Place of the drug in the therapeutic strategy
• 1st line treatment : docetaxel
• 2nd line treatment : docetaxel if responder or carbazitaxel
 ZYTIGA constitute an alternative to carbazitaxel with better tolerance
Targeted population
 Estimated to 4000 patients/year in France
77
NICE Assessment: Key conclusions
Study considered
Pivotal study : COU-AA-301
Criteria for an end-of-life treatment
• Short life expectancy (less than 24 months) without treatment,
• Potentially extension to life (at least 3 months) with treatment
• Small patient population
Key benefits
Can be taken orally at home
Cost effectiveness
• Expensive drug
• Not provided enough benefit to patients to justify the price the
NHS is being asked to pay
• Even with the discount that the manufacturer has offered
ICER = at least £ 63,200 /QALY
after taking into account the discount
Source : Abiraterone for castrationresistant metastatic prostate cancer previously treated with a docetaxel-containing regimen – February2012 – NICE draft guidance
78
NICE Assessment: Key conclusions
Clinical effectiveness
Clinically effective second-line treatment for castration-resistant
metastatic prostate cancer
Step change in treatment
• Is an oral drug taken by patients at home
• Is associated with few adverse reactions
Cost effectiveness
The manufacturer’s economic model closely adhered to the NICE
reference case for economic analysis.
ICER =
£ 47,200 /QALY < £ 50,000 /QALY
79
Source : Abiraterone for castrationresistant metastatic prostate cancer previously treated with a docetaxel-containing regimen – June 2012 – NICE technology appraisal guidance 259
IQWiG Assessment: Key conclusions
Research question
Benefit assessment according to the treatment of metastatic castrationresistant prostate cancerof adult men
Study considered
Pivotal study : COU-AA-301
IQWiG opinion
• Patient not eligible for further treatment with docetaxel :
 Considerable added benefit
• Patient still eligible for further treatment with docetaxel :
 Added benefit not proven (incomplete supplied file)
G-BA decision
• Patient not eligible for further treatment with docetaxel :
 Positive recommandation
• Patient still eligible for further treatment with docetaxel :
 Negative recommandation
80
Summary :
• DECISION
 Recommended
• PRICE = 3 400 € *
• DECISION
Positive opinion for MA dosage
and indication
Reimbursement = 100%
• DECISION
-
• PRICE = 3 613 € *
-
Patient not eligible for further
treatment with docetaxel :
Positive recommandation
Patient still eligible for further
treatment with docetaxel :
Negative recommandation
• PRICE = 5 403 € *
*120 tablets ⟺ 60 days
81
ASSESSMENT EXAMPLES
Gilenya®
82
Multiple Sclerosis :
Autoimmune disease
of central nervous
system :
- demyelination of
white matter
- axonal damage
Multifactorial disease
- autoimmun
- genetic
- environmental
- infectious
Epidemiology
- 2,5 Million people
- sex ratio : 2♀/1♂
- peak level at 30
Various forms :
- relapsing-remitting
- secondary progressive
- primary progressive
83
Source : www.vulgariz.com
RRMS
 Treatment strategy
84
Source : www.vidalrecos.fr
®
Gilenya
 Fingolimod
• Pharmacological class : Immunosuppressant
• Therapeutic Indication :
• Single disease-modifying therapy in highly active relapsing-remitting
multiple sclerosis for patient with :
• High disease activity despite treatment with IFN-β
• Rapidly evolving severe relapsing remitting multiple sclerosis
• Mechanism of action :
• metabolised by sphingosine kinase to the active metabolite fingolimod
phosphate
• Pharmaceutical Compagny :
Source : www.ema.com
85
®
Gilenya
 Assessment story
03/2012
Germany
01/2012
08/2011
06/2012
UK
France
UK
03/2011
MA (UE)
86
FREEDOMS – Phase III study
• Study
• Randomized, double blind, superiority study
• Comparing efficacity and tolerance of 0,5 mg and 1,25 mg fingolimod to that of
placebo
• In patients suffering from relapsing-remitting MS according to McDonald’s criteria,
having had at least one acute relapse in the year preceding the inclusion or at least
two in the two years preceding the inclusion.
• Endpoints
• Primary endpoint : Annualized relapse rate in 2 years
• Secondary endpoints :
•
•
•
•
% of patients without any disability progression
Number of new or newly enlarging T2-hyperintense lesions
Number of gadolinium-enhancing lesions on cranial MRI.
% of patients free of relapses
• Treatments
• 1272 patients randomised in 1:1:1 ratio , during 24 months
• 3 groups :
• Fingolimod 0,5 mg, PO
• Fingolimod 1,25 mg, PO
• Placebo, PO
87
FREEDOMS – Phase III study
• Results
• Conclusion
• Fingolimod
• more effective than placebo in reducing the number of relapses.
• lower dose as effective as the higher dose.
• reduced the risk of disability progression by 30% and also reduced brain lesion
activity as measured by MRI (at the lower, 0.5mg dose).
• The number of relapses per year among patients treated with fingolimod was around
half the number seen in patients given placebo.
88
TRANSFORMS – Phase III study
• Pivotal study D2302
• Multicentric, randomised, controlled, Double-blind, Double placebo
• Comparing efficacity and tolérance of fingolimod (0,5 mg and 1,25 mg) vs IFN-β1a
• In patients suffering from relapsing-remitting MS according to McDonald’s criteria,
having had at least one acute relapse in the year preceding the inclusion or at least
two in the two years preceding the inclusion.
• End Points
• Primary endpoint : annualized relapse rate (relapses include new, worsening or
reccurent neurologic symptoms)
• Secondary end-point :
• Number of new or enlarged lesions on T2 IRM at 12 months
• % of patients without any disability progression
• Treatments
• 1292 patients with relapsing-remitting multiple sclerosis , during 12 months
• 3 groups :
• Fingolimod 0,5mg, PO, daily
• Fingolimod 1,25mg, PO, daily
• IFN-β1 30µg, IM, weekly
Source : New England Journal of Medicine 362;5 January 20, 2010
89
TRANSFORMS – Phase III study
• Efficacy results at 12 months (Primary endpoint)
Significant reduction Fingolimod vs IFN-β1a
No difference between Fingolimod 0,5mg and
1,25mg
Annualized rate of relapse from baseline to 12 months
• Conclusion
• Superiority of oral fingolimod over intramuscular IFN-β1a
• reduction of annualized relapse rate (0,16 - 0,20 vs 0, 33)
• reduction of lesion activity and brain volume loss on MRI
• No difference in time to confirmed progression of disability
• Absence of dose-related differences requires further evaluation in the 2-years, placebo controlled
phase III trial
Source : New England Journal of Medicine 362;5 January 20, 2010
90
HAS/CT Assessment : Key conclusions
Studies considered
Pivotal studies : FREEDOMS and
TRANSFORMS
SMR important
• Multiple sclerosis is a chronic evolving disabling disease
• Preventive treatment for relapses and disability progression
• Efficacy/ADR ratio: moderate (2 years) / unknown (long term)
• Therapeutical alternatives exist: natalizumab and mitoxantrone
• Special interest for oral form limited by the need of surveillance
Infection, macular
oedema, hepatic
dysfunction,
cancer (skin ++)
ASMR IV
 ASMR : low, due to tolerance issue
Place of the drug in the therapeutic strategy
•
•
Mitoxantrone : aggressive forms
Natalizumab and Fingolimod : very active disease and severe form
with quick worsening
 case by case choice
Targeted population
 Estimated between 9000 and 11000 patients/year in France
91
HAS/CT Assessment : Key conclusions
Lack of efficacy data in the targeted population
New assessment scheduled after 1 year :
 with updated tolerance data
New data requested :
Follow-up data of French patients treated with GILENYA
Data submission no later than 2 years after registration
92
NICE Assessment : Key conclusions
Studies considered
Pivotal studies : FREEDOMS &
TRANSFORMS
Clinical effectiveness
No significant proof of benefit VS existing treatments (no study VS
Tysabri)
Cost effectiveness
Not judged cost-efficient, even after a discount
ICER gained =
£ 55,600/QALY
93
NICE Assessment : Key conclusions
Step change in treatment
•
• Valuable new therapy
Its oral formulation represents innovation in the treatment of
multiple sclerosis
Clinical effectiveness
Only part of the population covered by the marketing authorisation
for fingolimod was considered
Cost effectiveness
The manufacturer’s economic model could decrease the ICER to a
level that would be considered a cost-effective use of NHS
resources.
ICER =
£ 25,000 - £ 35,000/QALY
Source : Fingolimod for the treatment of highly active relapsing–remitting multiple sclerosis – April 2012 – NICE technology appraisal guidance 254
94
IQWiG Assessment : Key conclusions
Request from G-BA
Benefit assessment of Fingolimod in comparison with :
- Glatiramer acetate in patients with highly active RRMS who have failed to
respond to a full and adequate course of IFN-β
- IFN-β1a in patients with highly active RRMS, who have not received IFN-β
- IFN-β1a in patients with rapidly evolving severe RRMS
Studies considered
Pivotal study : TRANSFORMS only
Studies considered
• Complementary data provided by the company
 - Subgroup analysis from TRANSFORMS subpopulation
- Indirect comparison with glatiramer acetate
• TRANSFORMS : pivotal study compare fingolimod vs IFN-β in patients with
RRMS
 Data available only for 1 out of 3 subindications (patients with rapidly
evolving RRMS)
95
IQWiG Assessment : Key conclusions
IQWiG evaluation
• Patients with highly active RRMS, full previous treatment with IFN-β
- No evaluable data submitted by the pharmaceutical firm
 Added benefit of Fingolimod over glatiramer not proven
• Patients with highly active RRMS, incomplete previous treatment with IFN-β
- No evaluable data submitted by the pharmaceutical firm
 Added benefit of Fingolimod over IFN-β not proven
• Patients with rapidly evolving severe RRMS
- TRANSFORMS data
 Minor added benefit of fingolimod over IFN-β (because of best
tolerance)
G-BA decision
• Benefit assessment limited to 3rd population because of lack of data for other
populations and cardiac risks
 Reassessment of benefit assessment in 3 years
• Not recommended for patient with cardiac issues
96
Summary :
• DECISION
 Recommended
• PRICE = 1 705 € *
• DECISION
 Positive opinion for MA dosage
and indication
Health trusts approved
Reimbursement = 65 %
• DECISION
Conditions
-
• PRICE = 1 923 € *
-
Revaluation of benefice
assessment
Patient with cardiac disorder :
Negative recommandation
• PRICE = 2 325 € *
*28 capsules
97
Conclusion
98
Difficulties in Europe
• Companies have to deal with 2 main problems:
• Difficult macroeconomic environment
Important pricing pressure on pharmaceutical companies
• Discrepancies between data needed for obtaining MA & data
needed for market access
Assessment criteria for innovative medicines
Centralized
Local
EMA
HTA and competent bodies
Efficacy


Safety


Relative efficacy


Relative effectiveness

Local medical need

Ethical and social aspects

Cost-effectiveness

Post-marketing studies

Organizational aspects

Source : Bio Century – Week of February 18, 2013 – Volume 21.Number 7
99
Consequences for the companies
• Pharmaceutical companies need to anticipate HTA demands
to adjust their clinical development
• Choice of comparative drugs
• Choice of patients population/sub-populations
• Discussion with HTA as soon as possible
= phase II-III?
• Important costs for companies
= Companies may change their commercial approach in EU even if
it is the 2nd pharmaceutical market
New focus in emerging markets (BRICS)
Source : Bio Century – Week of February 18, 2013 – Volume 21.Number 7
100
EU harmonisation wish
• EUnetHTA - European network for Health and Technology Assessment
• Objective
• To put into practice an effective and sustainable HTA collaboration in
Europe
• To connect public national/regional HTA agencies, research
institutions and health ministries, enabling
• Effective exchange of information
• Support to policy decisions by the Member States
Globalize the evidence, localize the decision
101
EU harmonisation wish
• Domains of the HTA Core Model
1. Health problem and current use of technology
2. Description and technical characteristics
3. Safety
4. Clinical effectiveness
5. Costs and economic evaluation
6. Ethical analysis
R
A
P
I
D
F
U
L
L
7. Organisational aspects
8. Social aspects
9. Legal aspects
www.eunethta.eu - EUnetHTA - Joint Action 2010-2012
102
THANKS FOR YOUR ATTENTION
103