Creating collaborative systems to address orphan drugs in a sustainable way. The document discusses several European initiatives aimed at improving access to orphan drugs in a sustainable manner, including: 1. CAVOD (Clinical Added Value of Orphan Drugs) which aims to reduce the gap between marketing authorization and patient access through early dialogue and compiling evidence reports. 2. MOCA (Mechanism of Coordinated Access to Orphan Drugs) which seeks to create a shared mechanism between 15 countries to streamline pricing and reimbursement processes for orphan drugs. 3. The development of national plans for rare diseases in EU member states by 2013 to help coordinate diagnosis, treatment and research across countries. 4. Other

1. Creating collaborative systems to address orphan
drugs in a sustainable way – update from Europe
Wills Hughes-Wilson, VP Global Public Policy & Government Relations, Sobi
Member of the EU Committee of Experts on Rare Diseases (EUCERD)
Chair, Joint European Industry Task Force on Orphan Drugs (EuropaBIO + EBE)
Orphan Café, Leiden, 30 May 2012

2. Orphan Medicinal Products – “a balancing act”
2
• Sense of urgency
• High, unmet medical need
• Serious, life-threatening conditions
• But few patients, few data
• Risk:benefit = positive
• Acceptance that it is ethical to move forward
• (Regulatory) acceptance, despite overall weight of
evidence not so available
• Compared with more common conditions

3. Results of the approach =
drugs are being developed & approved
3
0
10
20
30
40
50
60
70
80
90
ODs with EU Positive Opinion ODs removed from EU Community Register
* 3rd Quarter 2011

4. “Balancing act” creates uncertainty –
and has an impact on all stakeholders
4
• Victims of success of the Regulation?
• ~55 therapeutic areas = “4,945 to 6,945 still to go?!”
• Governments seeking to understand the value of
what they are being offered
• How can we tell?
• Small datasets, surrogate endpoints, non-routine clinical
trial design, early approval…
• Some of the systems tried to date – NL – have
reportedly not been so successful for governments?
• “IS IT SUSTAINABLE?” Financially? Socially?

5. Creates a gap between Marketing Authorisation
(EU) & Access to Patients (Country / EU Member State)
5
Timeline graphic courtesy of Ernst & Young, CAVOD study, December 2011
Data Assessment Appraisal

6. This is important because…
6
• Customers – those who pay* – are thinking about
value
• What is it?
• How do they measure it?
• What is it worth?
* Gatekeepers to patient access…

7. Situating the approach to
orphan drugs in the wider external context
7
1. Evolving cooperative environment between HTA
bodies – cross-border cooperation
2. Legislation to address uncertainty – new
Pharmacovigilance legislation

8. “Orphan” & “non-orphan”
tools exist to make it possible
• “Cross-Border Healthcare
Directive” creates legal
framework for further
cooperation
• Rare Diseases as a focus
Healthcare provision
remains a Member State responsibility
…but no longer in isolation

9. 1. “Cross-Border Healthcare Directive” – 9 March 2011
9
• European reference networks (Article 12)
• Explicit focus in regular reporting (Article 20)
• Permanent Network of HTA bodies (Article 15)
• Rare Diseases as a particular focus (Article 13)

10. 2. New Pharmacovigilance Legislation
10
• …“post-authorisation efficacy studies where
concerns relating to some aspects of the efficacy of
the medicinal product are identified and can be
resolved only after the medicinal product has been
marketed”
• PRAC requirements captured in CHMP Opinion
• Post-Marketing-Authorisation data-gathering
• Coordination vital – building on early dialogue

11. What is true for drugs generally
is PARTICULARLY true for orphan drugs
11
October 2008: Grouping of 27 Member States agree
principles on orphan drugs as area of focus because
“these [orphan] medicines amplify strongly the
common tensions we have found in the field of
pricing and reimbursement: assessing and
rewarding innovation is difficult, budget
optimisation is challenged and access for patients is
limited in several countries”.

12. Countries facing the same questions –
Collaboration & cooperation as a way forward
12
• Particular need in the case of orphan drugs: rarity –
data & expertise
• Assessments need Methodologies & Agencies
• Takes time & resources
• Sharing / building something together rather than
creating de novo 27 times
• Best practice, experience
• Particular political focus on rare diseases & Orphan
Drugs with actions

13. European initiatives will interact to create
the framework for understanding orphan drugs
13
1. CAVOD – Clinical Added Value of Orphan Drugs
2. MOCA – Mechanism of Coordinated Access to
Orphan Drugs
3. EUCERD Work Programme
4. National Plans for Rare Diseases
5. …the future?

14. 1. CAVOD
14

15. Gap between Marketing Authorisation (EU)
& Access to Patients (Country / EU Member State)
15
Timeline graphic courtesy of Ernst & Young, CAVOD study, December 2011
Data Assessment Appraisal

16. Four key time-points in the process
of an orphan drug where collaboration could help
16
1. Early dialogue
2. Compilation report & evidence-definition /
Evidence-Generation plan
3. Follow up of the Evidence Generation Plan
4. Assessment of Relative Effectiveness
Respecting the roles and responsibilities within the
existing system
Breaking down “silos” – bridging the gap

17. Time
Orphan
Designation
Significant
Benefit COMP
Protocol
Assistance
CHMP Opinion
T0
EC Marketing
Authorisation
T0 + 90 days
T0+∆T
(after 3-5 years, flexible,
depending on 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
Early Dialogue
Compilation Report
& Evidence Needs Identification
• EMA
• EUnetHTA
• Sponsor
1st assessment
of Significant
Benefit
Confirmation of
Significant
Benefit
• EMA (Report)
• EUnetHTA
• EMA
• EUnetHTA
• MAH
Evidence generation Assessment
• EUnetHTA
• EMA
• Could be
implemented
already
• Actions required?
• Report could be implemented
immediately
• Involvement with PRAC
requirements needs more work
• Evidence generation plans
& follow-up would need to
be defined
• Other?
• Appropriate
methodologies / tools
for OMPs to be
developed

18. Characteristics to aid success
18
• Case-by-case
• Heterogenous conditions, therapies, situations
• Voluntary
• Respecting the systems, roles & responsibilities
• Multi-stakeholder involvement
• Developing the right tools for the job
• Measured
• Does it work? Periodic reporting

19. Formulating Policy into Reality:
where in the process & what next?
19
• 26-27 January 2012 – EUCERD endorses direction
• 9 May 2012 – updated by EUCERD drafting group
• 19 June 2012 – enlarged drafting group
• 20-21 June 2012 – EUCERD Plenary (adoption?)
[or November 2012 EUCERD meeting]
• Next steps from relevant authorities to implement
• Start with what we can: pilots by year-end?
“Oil in the machine”, not a new machine

20. 2. MOCA
20

21. Gap between Marketing Authorisation (EU)
& Access to Patients (Country / EU Member State)
21
Timeline graphic courtesy of Ernst & Young, CAVOD study, December 2011
Data Assessment Appraisal

22. Mechanism of Coordinated
Access to Orphan Drugs (MOCA)
22
• Create a tool for governments at time of pricing &
reimbursement
• Create (more uniform) access
• Control costs?
• “Whoever wants to give access” – have a “tool at
hand that he/she could follow”:
• From identification of potential solution (orphan drug)
• Through identifying what it’s worth
• To delivering to actual treatment of patient
• 15 countries – to create shared mechanism

23. 23
Mechanism of Coordinated Access
to Orphans
FR
UK
ESPT
IT
DE
CZ
BE
NL PL
RO
BG
EL
IE
HU
SE
FI
AT
CY
LT
LV
EE
DK
SKLU
SL
HR
SR
MK
BH
AL
CH
NO
UKR
UK
RUSSIA
TR
BY
IS
Will join
But it is not a closed club!
Member States can sign
up at any time to participate
in developing the mechanism
Shared mechanism between
the 15 countries involved

24. 24
Identifying and assessing
Relevant OMPs – procedural steps flowchart
Start: Rare Disease
Classification
Orphan Drug
Designation by COMP
Coordinated Horizon
Scanning
Early Dialogue
Advice Incorporated
into Clinical
Development Plans
Marketing
Authorisation
Application
Marketing
Authorisation Process
at EMA
CHMP Positive Opinion
Therapeutic / Scientific
Compilation Reports**
End: European
Commission Marketing
Authorisation
Early Access
Programmes
(regulatory or country
level driven)
Discussion with Member
States
*
*
*/**
*Potential links with other Work Packages
** Potential link with other initiatives in development, e.g. the different stages in the proposed CAVOD
process

25. Operational
step
Implementing
activity
Output
EU level:
EURORDIS
Patients
associations at
national level
ORPHANET
EPIRARE
Number of patients in
each country affected
by the (rare) disease
and elegible for
treatment with
orphan
Patient number
identification(PNI)
(Selection of the target
population)
PNI as orphan
medicinal
product
designation
PNI as
Patients`
Associations
PNI as Platforms
ad hoc and
European/nation
al Registries
Valuable
orphan
medicine
(WP1)
IRDIRC
National
centres of
reference
Analysis of pricing
systems for orphans in
MS
Actual costs of medicine/s
(transparentmechamism of
calculation)(Transparent
Pricing Matrix)
Rule-basedCeilling
price/thresholdper
drug/disease
Expenditure forecast
(affordability)
Framework
Agreement with an
award decision/
statement of ceiling
price and/or MEA)
National
procedures for
P&R (local MS
price)
National
reimbursement
and price decision
Joint
Procurement
Pricing/Procurement
(Funding mechanism)
Outcomes on
affordability,
costs and
profitability
Negotiations
based on health
impact*
Joint Reimbursement by
Health Impact Fund (for
innovation) and by member
states (for production costs)
Alternative
mechanism*The Health Impact Fund is a proposed new way of paying for pharmaceutical innovation. a firm agrees to provide its drug at cost where it is needed, and in exchange for foregoing the normal profits from
drug sales, the firm is rewarded based on the HIF’s assessment of the actual health impact of the drug. Payors would finance the HIF. See http://www.yale.edu/macmillan/igh/.
This scheme was developed for financing drugs in developing countries. However, it may be adapted for financing orphan drugs.

26. Parameter Lower Degree Medium Degree High Degree
1:2 000-1 to 1:20 000 1:20 000 to 1:200 000 less than 1:200 000
Number of Patients in EU (Pop. 500
000 000)
25 000 to 250 000 2 500 to 25 000 less than 2 500
Available Alternatives/Unmet Need
(Innovation)
yes, new drug does not address unmet
need
yes, but major unmet need still
remains
no alternatives except best supportive
care - new drug addresses major
unmet need
Relative Effectiveness, Degree of Net
Benefit (Clinical Improvement,
QoL, etc. vs. side effects) relative
to alternatives
incremental major curative
Response Rate (based on best avialable
selection criteria)
<30% 30-60% >60%
Degree of Certainty (Documentation) promising but not well-documented plausible unequivocal
Replaced by a proposed
multi-criteria approach to understand value?
…under discussion

27. Timelines & next steps
27
• 27 April 2012 – MOCA Topic Leaders finalise draft
• 11 May 2012 – workshop 15 countries +
stakeholders
• Summer 2012 – write-up of project proposals
• November 2012 – presentation of final report
• END-2012 – delivery of final product
• Final report
• TOOL
• Manual of definitions, objectives & instructions

28. 3. Specific approaches & programmes to build
systems for orphan drugs
28

29. Elements from Commission Communication will
combine to build true “Eco-System” for Orphan Drugs
29
CHAPTER 5 includes actions on:
• Centres of Expertise & EU Reference Networks
• Access to Orphan Drugs
• Compassionate Use programmes
• Incentives for Orphan Drug development
• Screening practices
• Diagnostic laboratories
• Research & development
• Registries & databases

30. Individual “how to” elements
being developed by the EUCERD
30

31. EUCERD: EU Committee of Experts on Rare Diseases
31
• 27 EU Member States (1 + 1 alternate)
• Patients
• Industry
• Academia / representatives of European-funded projects
• European Commission, ECDC
• EMA, COMP – request to be present
• 3rd Countries [non-EU]
The EUCERD’s role is to aid the European Commission
with the preparation and implementation of
Community activities in the field of rare diseases.

32. Individual “how to” elements
being developed by the EUCERD
32
• Quality Criteria on Centres of Expertise: Oct 2011
• Recommendations on CAVOD (under consideration)
• Draft Recommendations for European Reference
Networks (in process)
• New-Born Screening in Europe – proposals for next
steps (under discussion)
• …

33. 4. National Plans for Rare Diseases
33

34. Political commitment by 27 EU governments for
National Plan for RD in each EU Member State by 2013
34
If plans are similar,
they can link
together to create
a European area
for rare disease
diagnosis,
treatment,
research…

35. Collaborative work to build National Plans continues
35
• EUROPLAN recommendations adopted
• New EUCERD Joint Action (funding) includes further
work with countries
• 20 new conferences 2012-2013
• Indicators, measurables and success criteria
• EUCERD will report formally
• Potential benchmarking report by European
Parliament

36. 5. The future…?
36

37. The proposed Rare Disease treatment paradigm – the
model for the future of sustainable healthcare systems?
37
Commission
Communication
Council
Recommendation
Treatment
c
- Effective
- Cost-effective
- Sustainable
- Meeting payers’ needs
Centres
of
Expertise
Registries
c
Could this be the way forward for all innovative drugs?
Confirmed
Diagnosis
Dose
adjustment
Outcomes
CAVOD
HTA
(Rel. effectiveness)
Reimbursement
/ Reimb. revision
CUP / Reimb. (in dev.)

38. THANK YOU!
wills.hughes-wilson@sobi.com
38