An agency of the European Union Presented by: Jordi Llinares Head of orphan medicines Orphan drug designation in the European Union (EU) FDA/EMA Orphan

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


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






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



• 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







Outline


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


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)


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


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)


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


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


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






Outline


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


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


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



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)


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






Outline


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


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


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


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






Outline


Outcome of designations

Success rate ~70%


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%


Prevalence of Designated Conditions


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


Prevalence authorised orphan medicines

Granted MAs (68)

• <1 34

• 1-2 15

• 2-3 7

• 3-5 12


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


Where to have more information



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)



Many thanks

any questions?

[email protected]

EMA website: http://www.ema.europa.eu


Back up slides


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)


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


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


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


Activity protocol assistance


©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

Documents

An agency of the European Union Presented by: Jordi Llinares Head of orphan medicines Orphan drug designation in the European Union (EU) FDA/EMA Orphan