Grazie per aver scelto di utilizzare a
scopo didattico questo materiale
delle Guidelines 2011 libra.
Le ricordiamo che questo materiale è
di proprietà dell’autore e fornito
come supporto didattico per uso
personale.
Scientific process of
registration of new drugs
Prof. Mathieu Molimard
Department of Pharmacology
Bordeaux, France
Market access process
Marketing
authorisation
Market access process
Health technology
assessment
Marketing
Reassessment
1- Marketing authorisation : European Medicines Agency (EMA)
Efficacy / safety / quality
2- Market access : Need to demonstrate clinical value to payers
Based on Heath technology assessment : Scientific /economic evaluation
• Size of the clinical effect
• Place in the current therapeutic/prevention/diagnosis strategy
• Target population
- cost/efficacy (effectiveness is not available just after approval)
What is value ?
Relates to effect size
• The clinical effect is measured:
– Comparatively to a relevant comparator
– On a clinically relevant primary endpoint
– In a well defined target population
• The size of the effect:
– Is dependent on the target population
– Has to be of clear clinical significance
What is a relevant comparator ?
• The best treatment strategy available
(even non-drug if applicable)
• In line with the current recommendations
– to be harmonized at a European level,
– may differ from that of the US
• Adequate methology :
– double blind
– randomisation etc…
Clinically vs statistically significance
Statistical significance is necessary but not sufficient
p value
Decreasing size of the effect and clinical significance
0.05
0.01
0.001
…
0
Number of patients included
n= whole population
Schematically : The more patients to be included to reach
statistical significance the smaller the size of the effect looked for
Clinical meaningfull difference to be considered
Which clinically significant
threshold?
• Often defined by common sense and depends on:
–
–
–
–
–
natural history of the disease/unmet needs
considered endpoint
comparator pertinence
methodological considerations
Transferability of results to real life
• E.g. less than 2 months survival improvement in cancer that
includes 6 weeks treatment period may not be considered
clinically significant
Examples of threshold of clinical
significance for asthma and COPD?
• Trough FEV1 for COPD : improvement ≥ 100 ml
• Exacerbation rate ≥ 20% reduction in a patients
having 1/year… NNT≤5
• 6 minutes walking test :≥ 50 m
• TDI at least 1 point
• SGRQ at 4 point
• ….
Define the target population
• Define the best responders
– Role for pharmacogenetics,
– Role for therapeutic drug monitoring…
• ie : response to tyrosine kinase inhibitor is more linked to plasma
concentration than posology
• Consider test characteristics to define
responders (Se/Sp/PV, applicability…)
• Limit target population
– Increasing target population may decrease
the size of the overall effect … and pricing
Example : Market access in France
Commission de
la transparence
CEPS
Commercialisation
5 years
Reinscription
1- Commission de la transparence (CT) : Scientific and non-economic evaluation
Relative added therapeutic value
Place in therapeutic strategy
Target population
Public heath impact
Recommendation for reimbursement
3- Economic Committee (CEPS) : Economic evaluation
Pricing negotiation
Price volume agreement
CT Evaluation Criteria
• SMR : Medical value
– Reimbursement level
– Marketing authorization does not necessarily
imply reimbursement !
• ASMR : Medical added value
– Price
Are determined for each indication of a brand name
ASMR : medical added value
• ASMR : Amélioration du Service Médical Rendu
is based on
– Efficacy
– Tolerability
• Criteria taken into account : Size of effect
– Compared to previous recommended treatment(s) or
therapeutic strategy,
– With classical evaluation criteria
– Respecting good methodological practices
Medical added value (ASMR)
classification
• Ranking of ASMR from 1 to 5
–
–
–
–
–
ASMR 1 : major medical added value (1-2 /year)
ASMR 2 : important medical added value
ASMR 3 : moderate medical added value
ASMR 4 : minor medical added value
ASMR 5 : no medical added value (decrease in price)
• Based on the dossier
• Direct or indirect comparison with the current strategy
ASMR 1 to 3 implies reimbursement at « European price »
Decreasing effect and value
Which relevant endpoint ?
Example: cancer
• Overall survival +++
• Progression-free survival
•…
• Time to progression
• Weak intermediate criteria
• Quality of life (vs side effects…)
Decreasing effect and value
Which relevant endpoint ?
Example: Asthma/COPD
• Death
• Hospitalisation.
• Emergency room visit
• Exacerbation rate, oral steroids…
• FEV1, rescue medication, TDI, 6MWT
• Quality of life
Medical added value (ASMR)
classification
• ASMR 1 : major
– Glivec® (imatinib) : CML after interferon failure
• 50% major cytogenetic response at 8 and 9 months
• ASMR 2 : important
– Sutent® (sunitinib): metastatic renal carcinoma
• 5.5 months improvement of median progression-free survival
– Avastin® (bevacizumab) : metastatic colorectal carcinoma in
addition to Irinotecan + 5FU + folinic acid
• 5 months improvement of median overall survival
• 4 months improvement of median progression-free survival
Medical added value (ASMR)
classification
• ASMR 3 : moderate
– Avastin® (bevacizumab) : metastatic breast cancer
• 6 months improvement of progression-free survival
• But as comparator (paclitaxel) not usually recommended
(capecitabine/docetaxel) decreased ranking as moderate
• ASMR 4 : minor
– Iressa® (gefitinib): lung cancer first line + mutation
• 3.2 months improvement of median PFS (9.5 vs 6.3) vs
carboplatine/paclitaxel
Medical added value (ASMR)
classification
• ASMR 5 : no medical added value
– Tarceva® (erlotinib) : lung cancer (NSCLC) 2nd line
• 2 months improvement of median overall survival compared
to placebo
• No comparison to other approved second line treatment, i.e.
docetaxel
– Iressa® (gefitinib): lung cancer (NSCLC) 2nd line
• Median PFS non inferior to doxetaxel and non superior
Medical added value (ASMR)
classification COPD Asthma
• ASMR 4 : minor
– Asthma :
• Xolair
– COPD :
• Spiriva, Serevent
• ASMR 5 : no medical added value
– COPD
• Seretide, symbicort (compared to LABA)
• Onbrez (compared to LAMA and LABA)
Health technology assessment for reimbursement of
medicinal products by National Health Funds in Europe
France
Mandatory for any
drug/indication
Evaluation of clinical
benefit
Final decision maker
IQWIG
G-BA
X
(QALY)
±
X
X
X
Cost/
QALY
±
X
X
15%,35%
65%,100%
100%
CEPS
(clinical)
(economical)
X
X
X
(ASMR)
Reimbursement level
Target
population,
public health
impact
Germany
Local
trust
HAS
Cost/efficacy (/effectiveness
if available) evaluation
Price definition
UK
Price/
volume
agreement
negotiation
Ministry of Health
NICE
(Eng., Wales,
N.Irl.)
% Reference
price
Pound/QALY
Local/region
al
negotiation
NHS
X
X
G-BA
Conclusion
•
•
•
•
•
•
Market access requires reimbursement
Approval dossier is not a reimbursement dossier
Reaching statistical significance is not sufficient
Key effects must be of clinically significant size
Evaluation must be comparative to best strategy
Target population should focus to responders
• Still differences in health insurance systems/country