An agency of the European Union
Presented by: Jordi LlinaresHead of orphan medicines
Orphan drug designation in the European Union (EU)
FDA/EMA Orphan Designation and Grant Workshop FDA/EMA Orphan Designation and Grant Workshop
(12 Oct 2012)(12 Oct 2012)
European Medicines Agency 2012. 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: http://www.emea.europa.eu/htms/technical/dmp/copyritel.htm
Silver Spring, October 20122
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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
Outline
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 20124
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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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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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
Outline
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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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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• IncentivesCommission 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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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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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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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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Use of incentives 2011
Approximately use of 6 million Euro per year
Use of EU special contribution for orphan medicines (as percentage)
(2011)
28%
66%
5% 1%
Marketing authorisations Protocol assistance
I nspections Post-authorisation procedures
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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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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
Outline
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Designation criteria
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 EUEXCLUSIVE for EU
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NO
YES
“Prevalence” criterion “Seriousness” criterion
Prevalence
(≤ 5 / 10,000)
Insufficient return on investment
(costs > expected revenues)
Life-threatening or chronically debilitating
Life-threatening, seriously debilitating or serious and chronic
Available “methods” for diagnosis / prevention / treatment Significant
benefit / non satisfactory
“Existing methods” criterion
OR
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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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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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List of questions
DAY 60 (COMP meeting)
DAY 1
DAY 90 (COMP meeting)
Decision (European Commission)
Opinion
The designation process in the EU
Intent to file
letter
Application submission
Evaluation
JOINT FDA/EMA?
validation
Oral discussion
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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
Outline
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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
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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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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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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
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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
Outline
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Outcome of designations
Success rate ~70%
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OD by therapeutic field (2011)
COMP opinions by therapeutic area (2011)
Haematology5%
Oncology39%
Musculoskeletal and nervous
system17%
Other14%
Metabolism10%
Cardiovascular and respiratory
5%
I mmunology5%Anti-infectious
5%
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Prevalence of Designated Conditions
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Distribution by therapeutic area of authorised orphan medicines (n=68)
19%
4%3%47%
10% 1% 3%
10%
3%
A - alimentary tract and metabolism B - blood and blood forming organsC - cardiovascular system H - systemic hormonal preparationsJ - antiinfectives for systemic use L - antineoplastic and immunomodulating agentsN - nervous system R - respiratory systemV - various
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Prevalence authorised orphan medicines
Granted MAs (68)
• <1 34
• 1-2 15
• 2-3 7
• 3-5 12
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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
Where to have more information
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Where to have more information
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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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Many thanks
any questions?
EMA website: http://www.ema.europa.eu
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Back up slides
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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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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
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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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COMP: Orphan Designation
COMP and CHMP roles
Time
Knowledge
Judgement of Medical Plausibility
CHMP: Marketing Authorisation
COMP: Orphan Designation
Evidence of positive Benefit-Risk
Evidence of Significant Benefit
Prot. Assist
Scientific Advice WP
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Activity protocol assistance
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©European Medicines Agency 2012. 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: http://www.emea.europa.eu/htms/technical/dmp/copyritel.htm