1. Orphan drug designation in the European Union (EU)
FDA/EMA Orphan Designation and Grant Workshop
(12 Oct 2012)
Presented by: Jordi Llinares
Head of orphan medicines

2. European Medicines Agency 2012
European Medicines Agency Reproduction and/or distribution of this document is possible for non- commercial purposes provided that EMEA is always acknowledged as the source in each copy. Citations may be made, provided the source is always acknowledged. See: l.htm
Silver Spring, October 2012

3. Outline The European Medicines Agency Overview orphan designation
Orphan designation procedure and criteria
Definition of a medical entity
Significant benefit
Experience so far
Orphan designation
Marketing authorisation
Silver Spring, October 2012

4. Outline The European Medicines Agency Overview orphan designation
Orphan designation procedure and criteria
Definition of a medical entity
Significant benefit
Experience so far
Orphan designation
Marketing authorisation
Silver Spring, October 2012

5. A bit of history
EMA results from years of harmonisation for medicinal products in Europe
1965: First European Directive: foundation principles for authorisation of medicinal products for human use
1975: Second Directive: technical principles and creation of a scientific committee for medicinal products for human use (CPMP)
1993: Council Regulation (European System for Marketing Authorisation of Medicinal Products and European Agency)
1995: European Medicines agency opens in London
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6. The European Medicines Agency
EMA is an interface of co-ordination of Member States activities with respect to medicines (assessment responsibility for some procedures)
European Agency Decentralised Administration - not part of the European Commission (decision making body)
Centralized procedure: 1 application to the EMA  Marketing Authorization in all EU Member States
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7. Outline The European Medicines Agency Overview orphan designation
Orphan designation procedure and criteria
Definition of a medical entity
Significant benefit
Experience so far
Orphan designation
Marketing authorisation
Silver Spring, October 2012

8. Purpose of the Regulation
To set up system for designation of orphan medicines
To provide incentives for research, marketing and placing on the market designated orphan medicinal products
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9. Legal references in the EU
Regulation (EC) No 141/2000 of the European Parliament and of the Council on Orphan Medicinal Products of 16 December 1999
Criteria for designation
Committee (COMP)
Procedure
Incentives
Commission Regulation (EC) No 847/2000 of 27 April 2000
Commission communication July 2003 (2003/C 178/02)
Commission communication on Art 8(1) and (3) (C(2008) 4077)
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10. Main characteristics orphan designation
For medicinal products for human use
Procedure free of charge
Can be requested at any stage of development
Sponsor can be either company or individual
Established in the EEA (EU, Ice, Liech, Nor)
European Commission Decision gives access to incentives
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11. Incentives (I) Fee reduction / exemption
Extended incentives for Small and Medium Sized Enterprises (SMEs)
Market exclusivity (10 years)
Protocol assistance
Community marketing authorisation
National incentives (inventory from European Commission)
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12. Incentives (II)
10-year market exclusivity (+ 2 if paediatric indication – completion investigation plan)
Protection against
similar products
Molecular structure
mech of action
for same indication
Three derogations (access to market even if similar)
Sponsor’s consent
Lack of supply
Clinical superiority
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13. Use of incentives 2011 Approximately use of 6 million Euro per year
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14. Protocol assistance Protocol assistance
Protocol assistance  scientific advice
Questions on quality-efficacy-safety
Questions on significant benefit
Company position required
SAWP provides answers
CHMP adopts answers
COMP involved if issues on benefit
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15. Outline The European Medicines Agency Overview orphan designation
Orphan designation procedure and criteria
Definition of a medical entity
Significant benefit
Experience so far
Orphan designation
Marketing authorisation
Silver Spring, October 2012

16. Designation criteria EXCLUSIVE for EU
RARITY (prevalence) / RETURN OF INVESTMENT
Medical condition affecting not more than 5 in 10,000 in the EU (around 250,000 people)
Without incentives it is unlikely that the marketing of the product would generate sufficient return to justify the necessary investment
SERIOUSNESS
Life –threatening or chronically debilitating
ALTERNATIVE METHODS AUTHORISED
If satisfactory method exist the sponsor should establish that the product will be of significant benefit
EXCLUSIVE for EU
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17. OR “Prevalence” criterion “Seriousness” criterion Prevalence
(≤ 5 / 10,000)
Life-threatening or chronically debilitating OR
Insufficient return on investment
(costs > expected revenues)
Life-threatening, seriously debilitating or serious and chronic
“Existing methods” criterion NO
Available “methods” for diagnosis / prevention / treatment
Significant benefit / non satisfactory
YES
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18. Committee for Orphan Medicines (COMP)
1 elected Chair (Prof Bruno Sepodes)
1 Representative per Member State
3 Patients’ Representatives appointed by Eur. Commission
3 Members appointed by Eur. Commission on proposal from Agency
1 Member for Norway and 1 for Iceland
TOTAL: 33 members + 2 non voting
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19. Silver Spring, October 2012

20. COMP responsibilities
Give opinions on designation
Advise Commission on establishment and development of a policy on orphan medicinal products
Assist Commission in international liaison
Assist on guidelines
Contribute to Protocol Assistance (esp Significant Benefit)
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21. The designation process in the EU
Decision (European Commission)
Intent to file letter
Application submission
Evaluation
validation
Opinion
DAY 1
JOINT FDA/EMA?
DAY 60 (COMP meeting)
DAY 90 (COMP meeting)
List of questions
Oral discussion
Silver Spring, October 2012

22. Outline The European Medicines Agency Overview orphan designation
Orphan designation procedure and criteria
Definition of a medical entity
Significant benefit
Experience so far
Orphan designation
Marketing authorisation
Silver Spring, October 2012

23. Medical condition EC Guideline (ENTR/6283/00)
Any deviation(s) from the normal structure or function of the body, as manifested by a characteristic set of signs and symptoms (typically a recognised distinct disease or a syndrome)
Distinct: pathophysiology, histology, clinic presentation
Different severities- stages not acceptable
“Special considerations”
sub-setting (exclusive action)
Intersection ( New entity)
treatment modality
Silver Spring, October 2012

24. COMP policy on sub-setting from common condition
Usually not acceptable
Exceptionally if plausibility, rationale and prevalence of subset is well justified and documented
The COMP has refused subset of some applications based on severity stages: e.g. advanced Parkinson’s
The COMP has exceptionally accepted other subsets based on treatment modality (specific characteristic of drug administration), severity of disease: e.g. 2nd and 3rd degree burns
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25. Significant benefit
Significant benefit: “A clinically relevant advantage or a major contribution to patient care”
Based on assumptions at the time of orphan designation
Significant benefit over “satisfactory methods”
COMP to assess whether or not assumptions are supported by available data/evidence supplied by applicant
Sign benefit to be confirmed prior to marketing authorisation to maintain orphan status
Recommendation document on data for SB and plausibility
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26. Examples assumption for significant benefit
Clinically relevant advantage
Drug has a new mechanism of action: clinically relevant advantage to be justified/demonstrated
Opens possibilities for drug combination
Alternative therapeutic option
“complementary / better” safety profile
Major contribution to patient care
Improvement quality of life (e.g. alternative to dietary restrictions)
More “convenient” administration route
Age adjusted formulation
Silver Spring, October 2012

27. Outline The European Medicines Agency Overview orphan designation
Orphan designation procedure and criteria
Definition of a medical entity
Significant benefit
Experience so far
Orphan designation
Marketing authorisation
Silver Spring, October 2012

28. Outcome of designations
Success rate ~70%
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29. OD by therapeutic field (2011)
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30. Prevalence of Designated Conditions
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31. Distribution by therapeutic area of authorised orphan medicines (n=68)
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32. Prevalence authorised orphan medicines
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33. MA in ten years
75 orphan designated products authorised (68 “active” orphan medicines)
50% for orphan diseases affecting less than 1 in 10,000 patients
Average time OD to MA is 3 years
Authorisations
38% under exceptional circumstances
6% conditional approval
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34. Where to have more information
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35. Where to have more information
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36. Silver Spring, October 2012

37. Conclusions
Orphan designation is centralised in the EU  EMA Committee (COMP)
Applications to be submitted to EMA and assessed by COMP; designations by European Commission
Free of charge; need Sponsor is established in EU
99% agreement FDA-EMA regarding conditions
Significant benefit exclusive to EU: justifications to support claims (even at early stage)
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38. Many thanks any questions? Jordi.llinares@ema.europa.eu
EMA website:
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39. Back up slides
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40. Authorisation of an orphan drug
Based on same standards as for non orphan products (quality / safety / efficacy)
Authorisation only centralised procedure
CHMP responsible for assessment
Authorisation within designated condition
More than one designation possible per product (independent incentives)
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41. Specific requirements MAA (I)
Assessment of similarity (WHEN ORPHAN IS ON MARKET)
Applies if other orphan medicines authorised for same designated condition
Need to submit report in module 1.7
Molecular structure
Mechanism of action
Similarity of indication (“significant overlap of populations”?)
Assessment by CHMP working party competent
Final opinion by CHMP
Similarity can be triggered any time before EC decision
Proactive publication ongoing procedures
Silver Spring, October 2012

42. Specific requirements MAA (II)
Maintenance designation criteria
Report to orphan medicines section
At time of submission MA
Possible to update
Need to address all designation criteria
Standard set at time of authorisation
Assessment by COMP; opinion after MA opinion by CHMP
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43. COMP and CHMP roles Evidence of positive Benefit-Risk
Judgement of Medical Plausibility
Prot. Assist
Knowledge
Evidence of Significant Benefit
Time
COMP: Orphan Designation
Scientific Advice WP
CHMP: Marketing Authorisation
COMP: Orphan Designation
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44. Activity protocol assistance
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45. © European Medicines Agency 2012
© European Medicines Agency Reproduction and/or distribution of this document is possible for non-commercial purposes provided that EMEA is always acknowledged as the source in each copy. Citations may be made, provided the source is always acknowledged. See: tm
Silver Spring, October 2012