1. Creation of a mechanism for the exchange of knowledge on Clinical Added Value for Orphan Drugs (CAVOD) Meeting EUCERD October 24 th, 2011 Pascale Augé (former Ernst & Young), Head of Tech Transfer & Entrepreneurship, Institut Pasteur

2. 2011CAVOD StudyPage 2 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. The nine objectives of the study on the creation of a mechanism of exchange of knowledge on CAVOD (1/2) 1. To describe the regulatory process followed by an orphan medicine, from Orphan Designation at the European level to reimbursement in the Member State and examine to what extent the information produced by the authorities responsible for Orphan Designation and Marketing Authorization is directly useful for the medicine reimbursement decision process. 2. To describe the Health Technology Assessment expertise (focusing on relative efficacy and relative effectiveness) used at national level for this purpose and the level of involvement of existing international Health Technology Assessment networks. 3. To describe what expertise is used when the medicine is prescribed to all the targeted population of patients affected by a certain rare disease and how the heterogeneity of a disease expression is appraised (e.g. differences of weight, age, clinical manifestations, history of treatments taken by each patient, differences of social situation, patient ability to comply with the constraints imposed by the treatment, etc.), with the aim to identify the data collection which could be considered as acceptable to establish the relative effectiveness and, based on this data, to generate an assessment of real clinical added value. 4. To propose a format for the Common Assessment Report for clinical added value for orphan medicines structured in a usable way for national decision makers, keeping in mind that this Common Assessment Report should be flexible enough to be used for the revision of this report.

3. 2011CAVOD StudyPage 3 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. The nine objectives of the study on the creation of a mechanism of exchange of knowledge on CAVOD (2/2) 5. To define, in consultation with the EC competent Units, the European Union Committee of Experts on Rare Diseases (EUCERD), EMA, COMP and other EMA Committees (CHMP, CAT and PDCO), which is the most appropriate structure for performing this Task at a coordinated EU level: (a) Which could be the most appropriate mechanism of coordination with the HTA organizations in Europe, the COMP and other EMA committees, in terms of governance and in order to obtain the highest scientific added value? (b) Which could be the most appropriate composition of this mechanism of coordination? (c) What are the financial implications for setting up a new structure or using an existing structure? 6. To formulate recommendations for principal Tasks of this mechanism of coordination taking into account that expressed opinions should be in the form of non-binding Common Assessment Reports on the scientific assessment of the relative effectiveness of orphan Medicines approved at the EU level and for the set up of the modus operandi of the dialogue with Member States to facilitate coordination of possible additional national requirements (e.g. registries, real life studies). 7. To propose possible articulation between these Common Assessment Reports on the Clinical Added Value of Orphan Medicines and CHMP (Committee for Human Medicinal Products) post-marketing obligations to avoid duplication and make the most of available resources. 8. To stick to what can be implemented within the current legislative framework on pharmaceutical products, including the role of EMA. 9. To envisage potential enlargement of these assessment and related mechanisms of cooperation to the broader context of HTAs and to all types of medicines, not just orphan medicines.

4. 2011CAVOD StudyPage 4 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Centers of Expertise (CE) for Rare Diseases & European Reference Networks (ERN) Facilitating decision-making process for market access of orphan drugs EMA: COMP, CHMP protocol assistance, risk management plan Europlan & national plans for Rare Diseases EUnetHTA Joint Action I & II EUCERD Tapestry Networks - Pilots of multi- stakeholder consultations in early- stage drug development EuroScan Corporate Social Responsibility project with DG Enterprise, EC Basic principles of the CAVOD process CAVOD main objective: to facilitate MS informed decision on the scientific assessment of the clinical effectiveness of an orphan drug Geographical scope: EU level & institutions and the 27 member state (MS) CAVOD project takes into account and build on the basis of and in partnership with existing previous and simultaneous initiatives or structures on orphan drugs development, HTA and market access:

5. 2011CAVOD StudyPage 5 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. CAVOD process The CAVOD process will contribute to make a bridge and develop a continuum between pre- market authorization practices (clinical development) at EU level and post-marketing authorizations practices at member state level: The CAVOD mechanism should also help to bridge the gap between regulators and HTA bodies CAVOD process Positionning of the CAVOD process Pre-clinical phases Clinical Trials Marketing Authorization process Economic evaluation of HTA Pricing / Reimbur- sement Product launch Marketing Authorization (MA) Post-Marketing Authorization phasesPre-Marketing Authorization phases Pre-clinical phases Clinical Trials Economic evaluation of HTA Pricing / Reimbur- sement OD Product launch Pre-Marketing & post-Marketing Authorizations phases Marketing Authorization process CHMP positive opinionMarketing Authorizations(MA) at EC level and MS level CHMP positive opinionCOMP orphan designationCOMP re-assessment designation (significant benefit) Scientific evaluation of HTA COMP re-assessment designation (significant benefit) COMP orphan designation HTA reassess ment ….

6. 2011CAVOD StudyPage 6 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. General methodology Extensive data collection, via literature, interviews and questionnaires, on the regulatory processes (and particularly those applicable to orphan drugs) in the relevant institutions and national authorities involved in relative effectiveness assessment of drugs at MS level. Creating a trusted, solid and long-term relationship between the stakeholders (and in particular between EU and MS level stakeholders) through productive working sessions and workshops to reach a consensus solution that can be implemented in the future. Stakeholders worked together in a real committed way to develop the new proposal for the CAVOD process Defining the process associated with the CAVOD mechanism Evaluating the budget impact of this new process for the exchange of knowledge in terms of governance, operational function and decision-making process, in order to evaluate the cost of such mechanism. Drafting and finalizing the Final Recommendation report, including a format for the Common Assessment Report, CAR, for the scientific assessment of the relative effectiveness of orphan medicines.

7. 2011CAVOD StudyPage 7 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Update on the methodology Interviews/meetings with the 9 different types of stakeholders including: EC/EAHC EMA (COMP, CHMP, Secretariat) HTA national authorities in MS Payers (ESIP) European networks (EUNetHTA, HTAi, EUCERD) Patient organizations (EURORDIS…) Industry organizations (EBE, EFPIA…) Other initiatives (Orphanet, Swedish Presidency Initiative, national plan for RD…) Meeting with stakeholders: EUnetHTA (May 2011) EBE (Feb, May 2011) EFPIA (May 2011) EUCERD (Ocotber 2011) Questionnaires for the HTA national authorities including, among which: HTA bodies Government healthcare department officers Working sessions and workshop: 1 st working session: March 1 st CAVOD mechanism, model, structure and organization 2 nd working session: March 31 st, the relevant process and criteria for the scientific assessment of CAVOD 3 rd workshop: May 27 th, final workshop coupled with EURORDIS Round Table of Companies (ERTC) on the Mechanisms for the Implementation of the Clinical Added Value (Relative Efficacy or Relative Effectiveness) of Orphan Drugs, so called CAVOD

8. 2011CAVOD StudyPage 8 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. 19 attendees at the 1st working session on CAVOD mechanism, model, structure and organization NAMEOrganization Hans-Peter DaubenDIMDI François MeyerHAS Meindert BoysenNICE Wim GoettschCVZ Domenica TaruscioISS Flaminia MacchiaEURORDIS Marc Bogaert Plan Belge pour Les Maladies Rares Iñaki Gutiérrez Ibarluzea EUROSCAN Carla HollakAMC UVA NAMEOrganization Francis PangSHIRE Ana PalmaGENZYME Jérôme BOEHM DG Sanco Anders Lamark Tysse DG Sanco Antoni MONTSERRAT MOLINER DG Sanco Matus Ferech DG Sanco Georgios Margetidis EAHC Kerstin Westermark EMA, COMP; MPA Eric Abadie EMA, CHMP AFSSAPS Hans-Georg Eichler EMA

9. 2011CAVOD StudyPage 9 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. 18 attendees at the 2nd working session on relevant process and criteria for the scientific assessment of CAVOD NameOrganizationNameOrganization Georgios MargetidisEAHCWim Goettsch HTA body (CVZ) / EUnetHTA WP5 Birthe Byskov-HolmEMA (COMP)François MeyerHTA body (HAS) Eric AbadieEMA (CHMP)Meindert BoysenHTA body (NICE) Hans-Georg EichlerEMA (Secretariat)Ulrich SieringHTA body (IQWIG) Yann Le Cam Patient association EURORDIS Claudio FrankHTA body (ISS) Flaminia MacchiaChristine LeopoldReimbursement body (GOEG) Carla Hollak EUCERD / AMC UVA Francis Arickx Reimbursement body (RIZIV / INAMI) Francis PangEBE / ShirePierrick RolletEBE / GSK Wills Hughes-WilsonEBE / GenzymeAlexandre DelacouxEBE

10. 2011CAVOD StudyPage 10 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. 81 attendees at the final workshop of the Eurordis – Ernst & Young Round Table of Companies (ERTC) Mechanisms for the Implementation of the Clinical Added-Value (Relative Effectiveness) of Orphan Drugs, CAVOD

11. 2011CAVOD StudyPage 11 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Definitions of clinical added value: relative efficacy / relative effectiveness (1) Relative efficacy is the extent to which an intervention does more good than harm under ideal circumstances, compared to one or more alternative interventions Relative effectiveness can be defined as the extent to which an intervention does more good than harm compared to one or more intervention alternatives for achieving the desired results when provided under the usual circumstances of health care practice. Efficacy…Relative efficacyRelative effectiveness Time of positive opinion of CHMP (T 0 ) T 0 + T (3/5 years) (1)Definitions aligned with :EUnetHTA JA WP5: REA of Pharmaceuticals, Draft Background review, April 2011 High Level Pharmaceutical Forum, Core principles on relative effectiveness, Dec 2010 In certain HTA practices, the terms « Clinical effectiveness » are also used Within rare diseases and in particular ultra-rare diseases, comparators may particularly be complex to handle

12. 2011CAVOD StudyPage 12 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Avoid duplications at EU level Open, rigorous and transparent system Flexible system Quick operational implementation Build on an existing system/initiative Preferred option: EUnetHTA 2 additional options (hCMD- EMA or EUCERD-EAHC) Contribution of stakeholders in a real open and committed way A process and not a new structure Run pilots as early as 2012 Basic fundamentals Scope & mandate of CAVOD mechanism (1/2)

13. 2011CAVOD StudyPage 13 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. CAVOD process associated with EUnetHTA current & future initiatives as the rare diseases arm, so called EUnetHTA- CAVOD. Central role shall be to: Exchange valuable and trustable information on rare diseases and drugs Develop and make available methodology and tools for scientific HTA assessment adapted for OD Proceed to the EUnetHTA-CAVOD assessment according to necessary time- points Organize continuous evidence collection for OD as post-marketing activities Secondary role shall be to: Act as a knowledge center and collect all possible information on rare diseases and healthcare solutions Contribute to developing a continuum between pre-market and post-marketing authorizations Be the first operational implementation phase of a process delivering at EU level relative effectiveness assessment dedicated to rare diseases A sub-group of EUnetHTA in charge of OD with a general function of linking with existing initiatives, projects, bodies & institutions for all matters relating to OD and dedicated HTA (EMA, national HTA bodies, EUCERD, MEDEV, PPRI, PHIS, HTAi, INATHTA, EURORDIS… ) Basic fundamentals Scope & mandate of CAVOD process (2/2)

14. 2011CAVOD StudyPage 14 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. The approach of the EUnetHTA-CAVOD process: « à la carte » system adapted for the various HTA bodies needs Additional evidence generation EUnetHTA-CAVOD analysis Methodology / Toolkit dedicated to orphan drugs Information exchange the information exchange primary layer would support member states in giving them the opportunity to access the most complete information on the orphan drug, the targeted pathology, the epidemiology (associated with EUnetHTA JA WP6 and EMA (SAWP, CHMP, COMP)) the methodology/toolkit dedicated to orphan drug secondary layer would support member states in giving a methodological support specific to orphan drug in order to run their own assessment (associated with EUnetHTA JA WP4 ) the EUnetHTA-CAVOD analysis layer would propose reports focused on relative effectiveness to MS which do not have the time and/or resource to run their own assessment and report (associated with EUnetHTA JA WP5) the additional evidence generation layer, would aim at proposing recommendations for post-marketing evidence generation addressing uncertainties based on National and European shared views (associated with EUnetHTA JA WP7 and EMA (CHMP)) A four-layer approach was proposed following interviews with key stakeholders in order to better fit with the needs of the different national authorities involved in health technology assessment (HTA) processes:

15. 2011CAVOD StudyPage 15 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Strong collaborations will be needed between the EUnetHTA-CAVOD process and other initiatives National HTA bodies and national authorities in MS EUCERD : WG on Public Health Indicators EMA : all data and reports EUCERD : Mapping of initiatives in the field of RD European Reference Networks : Centers of Expertise for RD EuroScan, PHIS, PPRI, MEDEV, ISPOR, ISPE : information-sharing initiatives Orphanet : Encyclopedia, database and directory National HTA bodies and national authorities in MS European Reference Networks : Centers of Expertise for Rare Diseases Industry : evidence manufacturer dossier EMA : CHMP, SAWP, protocol assistance, Risk management plan EUCERD : Coding and classification of RD, registry methodology and common criteria and framework European Reference Networks Tapestry Networks : platform for early advice Industry Additional evidence generation EUnetHTA-CAVOD analysis Methodology / Toolkit dedicated to orphan drugs Information exchange

16. 2011CAVOD StudyPage 16 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Ambition of the EUnetHTA-CAVOD process : early and long-term follow up A four periods approach was proposed following workshop with key stakeholders in order to: facilitate information exchange before the CHMP opinion (even at protocol assistance) and EC marketing authorisation between EUnetHTA and EMA deliver compilation report and evidence generation plan monitor and adapt the evidence generation plan perform the relative effectiveness assessment Time CHMP opinion, T 0 EC marketing authorisation T 0 + 90 days T 0 +ΔT (after 3 to 5 years, flexible depending of the disease) Period 1: for EMA / EUnetHTA coordination Period 2: for simple Compilation report & evidence generation plan Period 3: for follow up of the evidence generation plan Period 4: relative effectiveness assessment Protocol assistance Significant Benefit, COMP

17. 2011CAVOD StudyPage 17 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Time New evidence generation brindging the gap between EMA and HTA bodies Principle of EUnetHTA-CAVOD process, early and long- term process along the life cycle of an orphan drug EUnetHTA-CAVOD reports Information exchange and Methodology / toolkit for orphan drugs

18. 2011CAVOD StudyPage 18 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Interaction process to bridge the gap between pre- & post-marketing practices One or more representative(s) of EUnetHTA-CAVOD as permanent participant to COMP and associated COMP working groups One or more representative(s) of EUnetHTA-CAVOD as non-permanent participant to SAWP, PDCO, CAT, CHMP (on an adhoc basis) One/two representative(s) of COMP as permanent participant to EUnetHTA-CAVOD work (EUnetHTA assembly when rare diseases are concerned) One representative of SAWP, PDCO, CAT, CHMP as non-permanent participant to EUnetHTA- CAVOD work (on an adhoc basis) One representative of rare diseases patient organisation (EURORDIS) as permanent participant to EUnetHTA-CAVOD work One representative of rare disease specific patient organisation as non-permanent participant to EUnetHTA-CAVOD work (on an adhoc basis) One representative of manufacturer as non-permanent participant to EUnetHTA-CAVOD work (on an adhoc basis)

19. 2011CAVOD StudyPage 19 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Interaction process EUnetHTA-CAVOD/EMA from the protocol assistance to the MA & Risk management plan The objective of the interaction between EUnetHTA-CAVOD and EMA is to build a bridge and develop a continuum between pre-market authorization practices (clinical development) at EU level and post-marketing authorizations practices at member state level. Through this process, the National HTA bodies through EUnetHTA are engaged collectively and bring their experience together to give inputs and valuable requirement to the EMA prior to the Risk management plan. Member states will be able to contribute to the Risk management plan. Evidence requirement gathering from HTA bodies Writing of recommendation paper Identification of the project manager PM EUnetHTA-CAVOD Exchange of information with the rapporteur of OD at the CHMP Marketing Autorisation review process, prior to CHMP opinion Exchange of information with EUnetHTA-CAVOD PM * One EUnetHTA-CAVOD PM for 4 days (FTE) EMA Focused on HTA expectations for evidence generation Based on national HTA bodies experience of the disease &/or drug Recommendation paper for EMA * Discussion to consider at the CHMP committee including EUnetHTA- CAVOD PM ?

20. 2011CAVOD StudyPage 20 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Compilation report at T 0 : Factual presentation of all available information in a meaningful way The objective of the compilation report is to have a common format, which offers a factual presentation of all available information in a meaningful way and to make the most of stakeholders knowledge. This will be useful : To avoid duplication of work between HTA agencies To support in their assessment MS which have not enough time/resources To increase transparency by providing a EU central report At T0, CAVOD may focus on domains 1&2 and 6 to 9 when possible as there is often a limited amount of information for domains 3&4 Evidence requirementOrganisation Manufacturer report (optional) EMA data and documents developed under the scope of OD analyses by the COMP, CHMP, CAT, PDCO Clinical trials dossier Non EU information on the drug itself or on available alternative therapies Natural history of the disease Clinical nature and impact of the diseases Current management of the disease and therapy limitations Patient & clinical experts perspective Compassionate use information, … Compilation Report Template elaborated by the EUnetHTA-CAVOD scientific secretariat Implementation of a pilot with an orphan drug to be selected Keep flexibility Quality control role Dissemination EUnetHTA-CAVOD scientific secretariat Gathering the data within CAVOD partners Additional bibliography search Report drafting and writing 1 analyst (FTE) for 2 months EUnetHTA-CAVOD assembly: focused on quality control Timing 60-90 days, prior to MA from EC Involvement of the MA holder

21. 2011CAVOD StudyPage 21 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. European Evidence Generation Plan, EEGP Evidence requirementOrganisation EMA information input EPAR Risk management plan MS inputs Data generated by the evidence generated for the compilation report Rapid single assessments (HTA) preliminary elements of the OD established by MS (including value judgment & post-MA studies requirement) when possible EUnetHTA-CAVOD scientific secretariat Drafting of a briefing document / knowledge gap analysis Writing of the EEGP draft 1 analyst (FTE) for 1 month EUnetHTA-CAVOD assembly Identification and prioritization of uncertainties Recommendation for new evidence generation Timing At the time of MA from EC Involvement of the MA holder EEGP Recommendation for evidence generation to support relative effectiveness Additional requests on top of the B/R management plan Non-mandatory plan The objective of the European evidence research plan is to allow more consistency in terms of evidence generation between expectations of MS in alignment with EMA/PRA. CAVOD should identify information gaps, agree on the uncertainties, prioritize them and decide which new evidences are needed to perform a relative effectiveness assessment in the future The EEGP will propose studies on top of the studies proposed in the Benefit/risk management plan and will not be mandatory for companies

22. 2011CAVOD StudyPage 22 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Follow-up monitoring of the EEGP Evidence requirementOrganisation EMA information input Safety update reports from the EMA MS information input MS healthcare information systems MA holder input EEGP evidence generation results Other input (ERN …) Disease registries or equivalent EUnetHTA-CAVOD scientific secretariat Gathering the data Follow-up report drafting EUnetHTA-CAVOD assembly Validation of follow-up reports Analysis of any discrepancies in the EEGP Timing once a year Involvement of the MA holder Follow up monitoring Regular gathering & update of evidence generation according to EEGP (yearly basis) Template for the follow-up reports (flexible) Follow-up reports of evidences The objective of the follow-up monitoring project is to ensure a regular update on the generation of evidence to : monitor the feasibility of the EEGP facilitate the information-sharing on a specific orphan drug and rare disease/therapeutic indication that could be useful information for other orphan drugs or other rare disease conditions, prepare the relative effectiveness assessment performed at T+ T

23. 2011CAVOD StudyPage 23 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Relative effectiveness analysis at T 0 +ΔT Evidence requirementOrganisation Evidences generated according to: Risk management plan European Evidence Generation Plan Safety update reports from the EMA Follow up monitoring reports Target population Data extrapolation of T 0 to T 0 +ΔT Clinical end-points (efficacy and effectiveness) Choice of the control Survey/clinical outcomes EUnetHTA-CAVOD scientific secretariat Coordination with the manufacturer Synthesis of the RE analysis report EUnetHTA-CAVOD assembly Reviewer team of 6-8 people Drafting of the RE analysis report Review of the RE analysis report draft by the Co-Reviewer team Validation & opinion on relative effectiveness Timing : 6 - 12 months Involvement of the MA holder Relative effectiveness assessment Methodology based on the HTA core model and EUnetHTA WP5 REA Template elaborated by the EUnetHTA-CAVOD scientific secretariat Pilot with an OD The objective of the relative effectiveness (RE) assessment report is to perform an analysis of the relative effectiveness of a drug on the basis of the evidence generated through the risk management plan and the European Evidence Generation Plan

24. 2011CAVOD StudyPage 24 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Additional evidence generation CAVOD analysis Methodology / Toolkit Information exchange information exchange primary layer as a link between partners to centralize information Sources Manufacturer report (manufacturer submission, Current management of the disease and therapy limitations) Expert knowledge (Clinical nature and impact of the diseases, Current management of the disease and therapy limitations, Patient/ disease registries…) Clinical guidelines Publications by other HTA-organizations (Clinical nature and impact of the diseases, Current management of the disease and therapy limitations) Literature (Clinical nature and impact of the diseases, Current management of the disease and therapy limitations EPAR/NPAR Unpublished (raw) clinical data (Available compassionate use data/ ATU, Confidential data (Accessible data from MS healthcare information systems (e.g. Belgium)) Benefit/risk management plan & B/R safety update report(s) (starting 2012) EUnetHTA-CAVOD potential partners EMA : all data, reports and documents developed under the scope of drug analyses by the COMP, CHMP, CAT, PDCO, PRAC Information-sharing initiatives (EuroScan, PHIS, PPRI, MEDEV, ISPOR, ISPE) Orphanet : Encyclopedia, database and directory EUCERD : Mapping of initiatives in the field of RD European Reference Networks Eurordis Manufacturer Objective: collect data and information, provide repository

25. 2011CAVOD StudyPage 25 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Additional evidence generation CAVOD analysis Methodology / Toolkit Information exchange The type of evidences (1) covered by the clinical added value are based on the EUnetHTA JA WP4 & WP5 & HTA core model and adapted to the specificity of orphan drug 1. Health problem and current use of the technology 2. Description and technical characteristics of technology 3. Safety 4. Effectiveness 5. Costs, economic evaluation 6. Ethical aspects 7. Organizational aspects 8. Social aspects 9. Legal aspects the methodology/toolkit dedicated to orphan drug secondary layer Sources:Draft Backgroung review, EUnetHTA JA WP5: Relative Effectiveness Assessment (REA) of Pharmaceuticals; April 2011 EUnetHTA WP4 – HTA Core Model for Medical and Surgical Interventions, Dec ember 2008 (1) Approach aligned with the EUnetHTA JA WP5: REA of Pharmaceuticals, Draft Background review, April 2011:. WP5 model to be particularly considered as being part of rare diseases specificity already considered as part of EMA scope

26. 2011CAVOD StudyPage 26 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Assumptions for the cost of the CAVOD process

27. 2011CAVOD StudyPage 27 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Three scenarios & three different direct costs with the EUnetHTA option presenting the highest cost synergies Direct costs borne by CAVOD for each scenario from 2012 to 2022 Distribution of direct costs borne by CAVOD for each scenario in 2022 Other ? EUnetHTA EUCERD- EAHC CMD - EMA ScenariosScenario 1Scenario 2Scenario 3 Budget 2022 without synergies 2,9 m3,3 m3,1 m Budget 2022 with synergies 1 m2,6 m3 m

28. 2011CAVOD StudyPage 28 © 2010 Property of Ernst & Young Advisory – Confidential, in compliance with the principles stated in the Disclaimers. This presentation, reserved for your internal use, is indissociable from the contextual elements used as a basis for its elaboration and from the spoken comments accompanying it. Four pilots to set up & run in 2012 requiring the support of key stakeholders (EUnetHTA, EMA, MAH…) First Pilot to set up the process for the interaction and information exchange between EUnetHTA and EMA prior to the CHMP opinion, Second Pilot to run the CAVOD compilation report based on an OMP under final review by the CHMP for the marketing authorisation, Third Pilot on the development of the European evidence generation plan with an OMP under reception of a positive opinion of the CHMP including the Risk management plan Fourth Pilot to perform a EUnetHTA-CAVOD relative effectiveness assessment with one orphan drug that is already on the market in certain countries and that is about to be reviewed by one member state As part of these 4 pilots, EUnetHTA-CAVOD shall have to delegate representatives at the SAWP, the CHMP, prepare the designation of project manager within its current member representative EMA shall have to open its committees and working groups and in particular the CHMP and the SAWP to EUnetHTA-CAVOD representatives and delegate COMP and CHMP representatives to EUnetHTA, Manufacturing holders shall support the CAVOD process through the selection of four OMPs designated product ready to enter the adhoc period of the CAVOD process, EUnetHTA shall have to set up the EUnetHTA scientific secretariat dedicated to CAVOD and further develop the information exchange center as well as adapt the methodological aspects; EMA shall have to open its data and internal reports related to selected molecule to EUnetHTA-CAVOD representatives EUCERD shall share with EUnetHTA-CAVOD all information on RD and registry set up

29. Contacts: Ernst & Young Advisory, Paris, France Tour Ernst & Young Faubourg de l'Arche 92031 Paris-La Défense Cedex FRANCE