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

European Medicines Agency 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/copyrite l.htm Silver Spring, October 2012

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

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

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 Silver Spring, October 2012

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 Silver Spring, October 2012

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

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 Silver Spring, October 2012

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) Silver Spring, October 2012

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 Silver Spring, October 2012

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) Silver Spring, October 2012

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 Silver Spring, October 2012

Use of incentives 2011 Approximately use of 6 million Euro per year Silver Spring, October 2012

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 Silver Spring, October 2012

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

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 Silver Spring, October 2012

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 Silver Spring, October 2012

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 Silver Spring, October 2012

Silver Spring, October 2012

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) Silver Spring, October 2012

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

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

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

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 Silver Spring, October 2012

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 Silver Spring, October 2012

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

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

Outcome of designations Success rate ~70% Silver Spring, October 2012

OD by therapeutic field (2011) Silver Spring, October 2012

Prevalence of Designated Conditions Silver Spring, October 2012

Distribution by therapeutic area of authorised orphan medicines (n=68) Silver Spring, October 2012

Prevalence authorised orphan medicines Silver Spring, October 2012

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 Silver Spring, October 2012

Where to have more information Silver Spring, October 2012

Where to have more information Silver Spring, October 2012

Silver Spring, October 2012

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) Silver Spring, October 2012

Many thanks any questions? Jordi.llinares@ema.europa.eu EMA website: http://www.ema.europa.eu Silver Spring, October 2012

Back up slides Silver Spring, October 2012

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) Silver Spring, October 2012

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

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 Silver Spring, October 2012

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 Silver Spring, October 2012

Activity protocol assistance Silver Spring, October 2012

© European Medicines Agency 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.h tm Silver Spring, October 2012