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

Creation of a mechanism for the exchange of knowledge on Clinical Added Value for Orphan Drugs (CAVOD)Meeting EUCERD

October 24th, 2011

Pascale Augé (former Ernst & Young), Head of Tech Transfer & Entrepreneurship, Institut Pasteur

2011 CAVOD 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.


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.


Centers of Expertise (CE) for Rare Diseases & European Reference

Networks (ERN)

Facilitatingdecision-making process

for market access oforphan drugs

EMA: COMP, CHMPprotocol assistance, risk

management plan

Europlan & national plans for Rare Diseases

EUnetHTAJoint Action I & II

EUCERD

Tapestry Networks - Pilots of multi-stakeholder consultations in early-

stage drug developmentEuroScan

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:


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

ClinicalTrials

Marketing Authorization

process

Economic evaluation of

HTA

Pricing / Reimbur-sementProduct launch

Marketing Authorization (MA)Post-Marketing Authorization phasesPre-Marketing Authorization phases

Pre-clinical phases

ClinicalTrials

Economic evaluation of

HTA

Pricing / Reimbur-sement

OD Product launch

Pre-Marketing & post-Marketing Authorizations’ phases

Marketing Authorization

process

CHMP positive opinion Marketing Authorizations(MA) at EC level and MS level

CHMP positive opinionCOMP orphan designation COMP re-assessment designation (significant benefit)

Scientific evaluation of

HTA

COMP re-assessment designation

(significant benefit)

COMP orphan designation

HTA reassessment

HTA reassessment

….

….


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.


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:► 1st working session: March 1st

► CAVOD mechanism, model, structure and organization

► 2nd working session: March 31st, ► the relevant process and criteria for the scientific

assessment of CAVOD

► 3rd workshop: May 27th, ► 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”


19 attendees at the 1st working session on CAVOD mechanism, model, structure and organization

NAME Organization

Hans-Peter Dauben DIMDI

François Meyer HAS

Meindert Boysen NICE

Wim Goettsch CVZ

Domenica Taruscio ISS

Flaminia Macchia EURORDIS

Marc Bogaert Plan Belge pour Les Maladies Rares

Iñaki Gutiérrez Ibarluzea EUROSCAN

Carla Hollak AMC UVA

NAME Organization

Francis Pang SHIRE

Ana Palma GENZYME

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 AbadieEMA, CHMP

AFSSAPS

Hans-Georg Eichler EMA


18 attendees at the 2nd working session on relevant process and criteria for the scientific assessment of CAVOD

Name Organization Name Organization

Georgios Margetidis EAHC Wim Goettsch HTA body (CVZ) / EUnetHTA WP5

Birthe Byskov-Holm EMA (COMP) François Meyer HTA body (HAS)

Eric Abadie EMA (CHMP) Meindert Boysen HTA body (NICE)

Hans-Georg Eichler EMA (Secretariat) Ulrich Siering HTA body (IQWIG)

Yann Le Cam Patient association EURORDIS

Claudio Frank HTA body (ISS)

Flaminia Macchia Christine Leopold Reimbursement body (GOEG)

Carla Hollak EUCERD / AMC UVA Francis Arickx Reimbursement body (RIZIV /

INAMI)

Francis Pang EBE / Shire Pierrick Rollet EBE / GSK

Wills Hughes-Wilson EBE / Genzyme Alexandre Delacoux EBE


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”

List of participant Name Organisation

Jakub Adamski Ministry of Health Poland

François Anger ADDMEDICA France Francis Arickx National Institute for Health and Disability

Insurance Belgium Pascale Augé Ernst & Young France Fabrizia Bignami EURORDIS France Karin Blumer Novartis International AG Switzerland Anne-Mary Bodin EURORDIS France Jill Bonjean EURORDIS France Meindert Boysen Centre for Health Technology Evaluation,

NICE United Kingdom Giorgio Buseghin Chiesi Farmaceutici S.p.A. Italy

David Caponera Aegerion Pharmaceuticals, Inc. USA

Germano Carganico Rare Partners Srl Italy

François Cornu Aegerion Pharmaceuticals, Inc. France

Alvarez, Cuervo Virginia Pharma Mar, S.A. Spain

Stéphanie Daireaux Ernst & Young France

Dorica Dan Romanian National Alliance for Rare Diseases Romania

Hans-Peter Dauben DIMDI Germany

Ri De Ridder National Institute for Health and Disability Insurance Belgium

Emma Eatwell Genzyme Belgium

Hans-Georg Eichler European Medicines Agency (EMA) United Kingdom

Jennifer Farrugia Ministry of Health Care & the Elderly Pharmaceutical Policy & Monitoring, Directorate of Malta

Katia Finck Shire Pharmaceuticals, HGT France

Juan-Manuel Fontanet Universitat Autònoma de Barcelona Spain

Sylvain Forget Swedish Orphan - Biovitrum France

Marie-Christine Fortun Orphan Europe (Recordati group) France

Gatermann Ruediger CSL Behring Germany

Pamela Gavin National Organization for Rare Disorders (NORD) USA

Ruben Giorgino Helsinn Health Care Switzerland

Josie Godfrey National Specialised Commissioning Team, NHS United Kingdom

Alicia Granados Genzyme Spain

Lesley Greene COMP, EMA United Kingdom

Laura Gutierrez Celgene International Switzerland

Iñaki Gutiérrez Ibarluzea Basque Office for Health Technology Assessment Basque Country

Pertti Happonen Finnish Medicines Agency Finland

Adam Heathfield Pfizer United Kingdom

Thierry Heinrich Talecris Germany

Stéphanie Hoffmann Enobia Pharma Belgium

Birthe Holm COMP, EMA Denmark

Wills Hughes-Wilson Genzyme Belgium

Ulrike Jägle Novartis International AG Switzerland

Mohit Jain Talecris Germany

Ana Jerónimo INFARMED Portugual

Anna Korecka-Polak Agency for Health Technology Assessment in Poland Poland

Kateřina Kubáčková University Hospital Motol Czech Republic

Lucie Kutikova Amgen Europe Switzerland Yann Le Cam EURORDIS France Patrick Le Courtois European Medicines Agency (EMA) UK Lugdivine Le Dez Alexion Pharma Belgium Sprl Belgium Christine Leopold Austrian Health Institute Austria Kevin Loth Celgene International Switzerland Flaminia Macchia EURORDIS Belgium Georgios Margetidis The Public Health Executive Agency

Luxembourg Maria Mavris EURORDIS France Joan Mendivil Bayer Hispania, S.L. Spain Isabelle Mercier Millenium: The Takeda Oncology company

USA François Meyer Haute Autorité de Santé (HAS) France Fredrik Moen AstraZeneca Belgium Elena Molina Vázquez Swedish Orphan Biovitrum S.L. Spain

Antoni Montserrat European Commission/ DG Health and Consumers Luxembourg

Jean Mossman Mark Krueger & Associates, Inc. USA Hicham Naim Ernst & Young Switzerland Alan Newlands Clovis Oncology United Kingdom Gérard Nguyen Rett Syndrome Europe France Célia Oculi Ernst & Young France Francis Pang Shire Pharmaceuticals, HGT United

Kingdom Samantha Parker Orphan Europe (Recordati group) France Elisabeth Paternostre Sanofi-Aventis R&D France Fabien Peuvrelle Celgene International Switzerland Robert Pleticha EURORDIS France Massimo Radaelli ARIAD Pharmaceuticals, Inc. USA Pierrick Rollet GSK rare diseases United Kingdom Alric Ruether Institute for Quality and Efficiency in

Health Care Germany Peter Saltonstall National Organization for Rare Disorders

(NORD) USA Laura Sampietro Colom HTAi Spain Ad Schuurman Department of the Dutch Health Care

Insurance Board Netherlands Sylvie St-Laurent Pfizer France Jan-Maarten Ten Brundle Baxter World Trade Belgium Geraint Thomas GlaxoSmithKline United Kingdom Josep Torrent-Farnell COMP, EMA Spain Anders-Lamark Tysse European Commission- DG SANCO

Belgium Jutta Ulbrich Bayer Schering Pharma AG Germany Kerstin Westermark COMP, EMA Sweden Martine Zimmermann Alexion Europe France


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 efficacy Relative effectiveness

Time of positive opinion

of CHMP (T0)

T0 +T (3/5 years)

(1) Definitions aligned with : EUnetHTA JA WP5: REA of Pharmaceuticals, Draft Background review, April 2011High 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


►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)


►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)


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:


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



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, T0

EC marketing authorisationT0 + 90 days

T0+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


Time

Principle of EUnetHTA-CAVOD process, early and long-term process along the life cycle of an orphan drug


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)


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

EUne

tHTA

-CAV

OD

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 ?


Compilation report at T0: 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 requirement Organisation

• 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


European Evidence Generation Plan, EEGP


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 ECInvolvement 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


Follow-up monitoring of the EEGP


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 yearInvolvement 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


Relative effectiveness analysis at T0+ΔT


• 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 T0 to T0+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


Additional evidence

generation

CAVOD analysis

Methodology / Toolkit


“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


Additional evidence

generation

CAVOD analysis

Methodology / Toolkit


the “methodology/toolkit dedicated to orphan drug” secondary layer

Sources: Draft Backgroung review, EUnetHTA JA WP5: Relative Effectiveness Assessment (REA) of Pharmaceuticals; April 2011EUnetHTA 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


Assumptions for the cost of the CAVOD process

Candidates for each timing of CAVOD process 2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022Protocol assistance - Interaction with EMA 1 68 68 68 68 78 78 78 78 81 81MA application - Interaction with EMA & compil report 1 10 10 13 13 13 13 16 16 16 16MA granted - EEGP 1 6 6 8 8 8 8 10 10 10 10Follow up 0 1 7 13 21 28 30 32 34 36 38RE assessment 1 0 0 0 0 1 6 6 8 8 8Total number of candidates followed each year 3 79 85 94 102 120 127 132 136 141 143

Hypothesis of time/phase/candidate (in days) CAVOD group CAVOD Project Manager Scientific secretariatScientific advice 0,06 3 1

CHMP MA application 0,1 5 3COMP review of designation 0,1 2 1

Compilation report 0,15 1 25European evidence generation plan 0,3 2 8

0,05 0 0,50,3 20 12

Interaction with EMA

Compilation report & EEGP

Relative effectiveness assessment Follow up

Time/phase in 2022 (in days) CAVOD group CAVOD Project Managers Scientific secretariatInteraction with EMA 8,1 355 145Compilation report & EEGP 5,4 36 480Follow up 1 0 19RE assessment 4,8 160 96TOTAL 19,3 551 740


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 ?

EU

netH

TA

EUCERD- EAHC

CMD - EMA

0 €

500 000 €

1 000 000 €

1 500 000 €

2 000 000 €

2 500 000 €

3 000 000 €

3 500 000 €

2012 2013 2014 2015 2016 2017 2018 2019 2020 2021 2022

Scenario 1 - EUnetHTA Scenario 2 - CMDh like Scenario 3 - EAHC

196 837 € 380 119 €157 300 €800 998 €

921 998 €376 297 €

537 567 €

537 567 €800 000 €

800 000 €

268 783 €

459 579 €

352 066 €

0 €

500 000 €

1 000 000 €

1 500 000 €

2 000 000 €

2 500 000 €

3 000 000 €

3 500 000 €

Scenario 1 -EUnetHTA

Scenario 2 - CMDh like

Scenario 3 - EAHC hosting

Surveillance committee

Administrative functions

External experts for RE assessment

Scientific secretariat

Project Manager - interaction with EMA

Principal group meetings

Scenarios Scenario 1 Scenario 2 Scenario 3

Budget 2022 without synergies

2,9 m€ 3,3 m€ 3,1 m€

Budget 2022 with synergies

1 m€ 2,6 m€ 3 m€


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

Contacts: Ernst & Young Advisory, Paris, France

Tour Ernst & YoungFaubourg de l'Arche92031 Paris-La Défense CedexFRANCE

Documents

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