1. 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.

2. Scientific process of registration of new drugs Prof. Mathieu Molimard Department of Pharmacology Bordeaux, France

3. Market access process Marketing authorisation Market access process Health technology assessment Marketing Re- assessment 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)

4. 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

5. 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…

6. Number of patients included p value n= whole population 0.05 0.01 0.001 … 0 Clinically vs statistically significance Statistical significance is necessary but not sufficient Decreasing size of the effect and clinical significance 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

7. 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

8. 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 ….

9. 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

10. 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

11. 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

12. 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

13. 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 »

14. Which relevant endpoint ? Example: cancer Decreasing effect and value Overall survival +++ Progression-free survival … Time to progression Weak intermediate criteria Quality of life (vs side effects…)

15. Which relevant endpoint ? Example: Asthma/COPD Decreasing effect and value Death Hospitalisation. Emergency room visit Exacerbation rate, oral steroids… FEV1, rescue medication, TDI, 6MWT Quality of life

16. 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

17. 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

18. 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

19. 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)

20. FranceUKGermany HAS (clinical) CEPS (economical) NICE (Eng., Wales, N.Irl.) Local trust IQWIGG-BA Mandatory for any drug/indication XX Evaluation of clinical benefit X (ASMR) X (QALY) ±XX Cost/efficacy (/effectiveness if available) evaluation X Cost/ QALY ±XX Reimbursement level 15%,35% 65%,100% 100% % Reference price Price definition Target population, public health impact Price/ volume agreement negotiation Pound/QALY Local/region al negotiation XX Final decision maker Ministry of Health NHS G-BA Health technology assessment for reimbursement of medicinal products by National Health Funds in Europe

21. Conclusion M arket access requires reimbursement A pproval dossier is not a reimbursement dossier R eaching statistical significance is not sufficient K ey effects must be of clinically significant size E valuation must be comparative to best strategy T arget population should focus to responders Still differences in health insurance systems/country