Rare Diseases and Orphan Medicinal Products Máster en diagnóstico y terapia de las enfermedades raras Josep Torrent-Farnell Universitat Autònoma de Barcelona Hospital de la Santa Creu i Sant Pau Comité de Medicamentos Huérfanos, EMEA, Londres 22 marzo 2010 Universidad Internacional de Andalucía

Why a regulation for Orphan Medicines is needed? Some conditions occur so infrequently that the cost of developing a medicinal product would not be recovered by the expected revenues. Therefore the pharmaceutical industry is unwilling to develop these medicines under normal market conditions. Patients suffering from rare conditions should be entitled to the same quality of treatment as other patients (EC Regulation No 141/2000)

Some facts on rare diseases (I) More than 6,000 rare conditions have been identified (WHO) People affected by Orphan diseases(*) USA: 20 million EU: 25-30 million Spain: 3,5 million (*)Estimate figures

Some facts on rare diseases (II) More than 4,000 rare conditions are genetic in origin and affect paediatric population People affected by inborn rare diseases 1/3 will die during the first year of life 1/3 will be handicapped for the span of life 1/3 will receive the most suitable treatment and have an acceptable quality of life

Some facts on rare diseases (III) A major public health burden recognized as a health priority by the EU (DG SANCO and DG Research) Causing severe deficits*: Motor (44 % of all RD) Chronic pain (22 %) Intellectual (6.5 %) Long-term permanent disabilities*: Undermining QoL/autonomy Partial limitations (37 %) Restricted autonomy (30 %) Reduced activity (23 %) Lack of autonomy (6 %) * Data from Orphaned database

Some facts on rare diseases (IV) An heterogeneous group of different clinical conditions affecting potentially all organs and systems of the body and all ages. They are life-threatening, serious and/or chronically debilitating, impairing QoL and causing long-lasting disabilities and dependences. They are “invisible” by the society and often “unknown” by health professionals. Requires a multidisciplinary approach for its overall management (genetic screening, pharmacologicals, surgery,nutraceuticals, rehabilitation, specific educational strategies, and social support).

Orphan conditions (RD) vs neglected diseases Neglected diseases are medical conditions (severe, life-threatening and chronically debilitating) that have a high prevalence in developing regions (“poor countries”) but they display a low prevalence in developed regions (“rich countries”) Some examples are: Tuberculosis, Malaria, HIV/SIDA, Chagas disease, Leihmaniasis Buruli ulcer, sleep sickness, etc.

Some examples of Rare Diseases* Hodgking and non-Hodgking Lymphomas All types of Leukemias More than 400 solid cancers conditions Multiple Mieloma Sarcoidosis Graft-versus-Host Diseases Duchene Muscular Distrophy Friedreich Ataxia Leber Hereditary Optic Neurophaty (LHON) Laron Syndrome ELA Pompe Disease Nieman-Pick-Disease Gaucher Disease Fabry Disease Polyarteritis Nodosa Mucopolysaccharidosis Thalasemias Ewing Sarcoma Churg-Strauss Syndrome * NORD, EURORDIS, ORPHANET, databases

Some examples of “Ultra Rare Diseases” > 1000 cases* Cohen Syndrome Larsen Syndrome Seckel Syndrome Gunther Disease Kimura Disease Ondine Syndrome Möbius Syndrome Coffin-Siris Syndrome CHILD Syndrome Li-Fraumeni Syndrome * NORD, EURORDIS, ORPHANET, databases

Unmet medical needs for patients affected by rare disorders require global and international joint efforts

Orphan Medicinal Products: International Overview United States ‘Orphan Drug Act’ 1983 Japan ‘Orphan Drug Legislation’ 1993 Singapore ‘Orphan Legislation’ 1997 Australia ‘Orphan Legislation’ 1998 Europe ‘Orphan Regulation’ 2000

Orphan Medicinal Products in the EU International Comparison

Comparative Requirements for ODD US EU Epidemiological “prevalence” Nature of disease 6.8 / 10,000 Rare 5 / 10,000 Life-threatening, debilitating Scientific rationale YES Economic (lack of ROI) Significant benefit (added therapeutic value) “Medically plausible” subset Time of application Medical devices NO Before MA Humanitarian use

Comparative Requirements for ODD US EU Market exclusivity (yrs) 7 10 MA fee–waiver YES Protocol assistance/ scientific advice Direct grants from regulatory agency YES (Clinical studies) NO Other public grants YES (NIH) YES (DG Research, National) Tax credits YES (50% of clinical cost) Depends on MS

Orphan Medicinal Products: Legal Basis Legal Basis Medicinal Products Council Regulation (EEC) 2309/93 Council Directive 2001/83/EG European Pharmacopoeia Legal Basis Orphan Products EUROPEAN PARLIAMENT and COUNCIL REGULATION (EC) No 141/2000 COMMISSION REGULATION (Ec) No 847/2000

Orphan Medicinal Products: Designation vs. Authorization (I) ensuring that only medicinal products that are effective, safe and of good quality are marketed. Designation providing incentives for the development of medicinal products for the benefit of patients suffering from rare conditions

Orphan Medicinal Products: Designation vs. Authorization (II) Level of proof: Authorization scientifically proven fact (beyond reasonable doubts) Designation reasonable scientific assumptions (hypothesis based on solid scientific facts)

Some basic considerations (I): Designation Given by COMP is the “ENTRY GATE” and gives access to several incentives and to centralised system Epidemiological criteria (“one in two thousand”) Does not lower the requirements when submitting and application for M.A. Are mainly intended to mobilise partnering and funding for investigation in rare diseases Several different (or “sameness”) active substances can be designated for one specific orphan condition

Some basic considerations (II): Marketing authorizations Are given by the CHMP assessment on the quality, safety and efficacy data submitted for centralised applications Orphan-market-exclusivity rights are linked to the approved therapeutic indication by the CPMP Prevents “me-too” drugs entering to the EU market

Orphan Medicinal Products Orphan Condition Any deviation from the normal structure and function of the body, as manifested by a characteristic set of symptoms, typically a disease or syndrome. Benefit from incentives Therapeutic Indication It will be the result of the assessment of the quality, safety and efficacy data submitted with the marketing application It may be more restrictive than the orphan condition Benefit from market exclusivity rights

COMP Composition The regulation establishes the Committee for Orphan Medicinal Products (COMP), within the EMEA, which is responsible for examining all applications for orphan medicinal product designation submitted to it in accordance with the Regulation. 33 Members: One member nominated by each of the Member States (27) Three members nominated by the Commission to represent patients’ organisations (3) Three members nominated by the Commission on the basis of a recommendation from the Agency (3)

Designation means investigational orphan products Task of the Committee Scientific evaluation: Orphan drug designation Protocol assistance (through SAWP) Significant benefit at the time of granting MA 5 years review (economic evaluation upon request from MS) Public health activities: Advice Commission to establishment develop OMP policy Liaising internationally and liaising with patient groups Assist Commission in preparing guidelines EU Experts Network/ Increase visibility Designation means investigational orphan products

Marketing Authorisation EMEA COMP CHMP Advice on designation Protocol Assistance Scientific Advice EU Panel Experts rare diseases Review Applications Review Applications Marketing Authorisation Designation ‘Entry Level’ ‘Outcome’

Orphan Designation Criteria Identifies ‘orphan’ products eligible for incentives Application from sponsor should demonstrate:  life-threatening or debilitating nature of condition  medical plausibility  prevalence < 5 in 10,000 or unlikely to generate sufficient return on investment no satisfactory methods exist or medicinal product will be of significant benefit COMP Opinions EC Designations

Comparative US/EU Criterion for Orphan Drug Designation Common Epidemiological (prevalence) (7/10.000 US; 5/10000 EU) Economic (unlikely to generate sufficient return on investment) Medical plausibility of the condition Biological/pharmacological rationale Sub-setting (salami-slicing strategy):exceptional EU only Assumption of significant benefit Existing methods are not satisfactory

Orphan Medicinal Products in the EU The Incentives (non exhaustive): Market exclusivity Protocol assistance during the development, with involvement of the CPMP Access to the Centralized System (independent of List A/B) Fee reduction for centralised applications (and marketing authorisation maintenance activities) Priority access to EU research programs National incentives (grants, tax reductions) SME’s Office (EMEA)

Comparative US/EU Incentive for Orphan Designated Products Common Market exclusivity rights Scientific Advice / Protocol Assistance/ SME’s Fee-waivers Specific for US Tax credit FDA grants Specific for EU Direct access to centralised procedure Priority access to EU research programs National incentives and measures

Orphan Medicinal Products in the EU Period of ten years exclusivity from the date of marketing Conditions orphan designation AND marketing authorisation throughout EU Scope of exclusivity no market authorisation for similar medicinal products in the same indication(s)

From: REGULATION (EC) No 141/2000 Article 8, Market exclusivity Where a marketing authorisation in respect of an orphan medicinal product is granted pursuant to Regulation (EEC) No 230993.. <cut>.. The Community and the Member States shall not, for a period of 10 years, accept another application for a marketing authorisation, or grant a marketing authorisation or accept an application to extend an existing marketing authorisation, for the same therapeutic indication, in respect of a similar medicinal product.

Significant benefit Normally in terms of improved efficacy and/or safety and/or contribution to patient care Exceptionally, potential availability can be taken into account, e.g. A product authorised in all Member States as opposed to a product authorised only in one or very few Member States

Defining a condition (I) Exceptionally subsets as valid conditions: A subset of a (frequent) disease could be considered a valid condition if patients in that subset present distinct evaluable characteristic(s) with a plausible link to the condition and if such characteristics are essential for the medicinal product to carry out its action the absence of these characteristics will render the product ineffective in the rest of the population

Defining a condition (II) Generally invalid subset: Different degrees of severity or stages or localization of a disease A subset of patients within a condition in whom the product is expected to show a favorable benefit/risk

The “salami-slicing” and “evergreening” approaches are aimed to: Fragment the population into “artificial” subsets within a disease/condition To meet the prevalence criteria by creating a “non-true” population subgroup To benefit from market-exclusivity rights To attempt to lowering usual requirements for the submission of an application for M.A. To gain additional exclusivity rights by adding subsequent new-non-well justified target populations (“the evergreening tactic”)

Subsetting a medical condition:“salami-slicing strategy” Total >5/10.000 “Subset” <5/10.000 No Yes Prevalence criteria

Medically Plausible Subsets (I) The true disease process. The seriousness of the condition The inherent characteristics of the drug The mechanism of action of the drug Unique characteristics of the patient population

Medically Plausible Subsets (II) Questions to address: Is the subset a “real” sub-population? Eg., not a stage of the general disease category? Why should the drug be limited to this subset? Are there characteristics of the larger patient population which exclude them from this treatment? Will the drug be useful in the larger population? Is the selection criteria in clinical trials acceptable ?

ORPHAN DESIGNATION - How to Apply Sponsors to notify EMEA of intent to submit at least 2 months prior to filing Sponsors are encouraged to request a pre-submission meeting with EMEA prior to filing Co-ordinators (1 COMP, 1 EMEA) and expert(s) will be appointed Applications to be prepared in accordance with Guideline on Format and Content of Applications for Designation

Orphan Medicinal Products in the EU The procedure A sponsor submits the application to the EMEA * the EMEA validates the application (day 1) the EMEA prepares a summary report the EMEA COMP adopts an Opinion (by day 90) the EU Commission adopts a Decision (30 days) *Pre-submission meetings with EMEA highly encouraged

Protocol assistance 3 Representatives of the COMP are members of the Scientific Advice Review Group since January 2002. They are responsible for the evaluation of Questions related to significant benefit. In these cases the significant benefit responses are discussed and adopted by the COMP and the scientific advice letter is co-signed by the two Chairpersons

Non authorised products are available in the EU Dealing with the three possible scenarios for orphan designation Non authorised products are available in the EU Evidence-based rationale needed Existing treatments are available in the EU “Assumption of significant benefit” or “Existing methods are not satisfactory” When a designated products holds a community authorisation A “similar” should demonstrate “clinical superiority” to the existing one

Proposed Orphan condition Redefine Medical Plausibility No Yes No Prevalence justification < 5/10.000 Yes Satisfactory methods Yes No Assumption on Significant benefit Overall Rationale No Yes Negative opinion No Yes Designation

SUMMARY OF ORPHAN DRUGS

Estatus huérfanos Unión Europea - Investigacional 1085 Solicitudes de designación de medicamento huérfano 743 Designaciones (90 solicitudes/año) Desde 2000 el promedio de éxito es del 72% En el último año el porcentaje de solicitudes positivas es del 75 % 713 Decisión Comisión Europea 261 Actividades realizadas 15 negativas © EMEA (Abril 2000- Febrero 2010)

Status of Orphan Applications 14/04/2017 Status of Orphan Applications 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 Total No. of applications submitted 72 83 80 87 108 118 104 126 119 164 1061 Positive COMP Opinions 26 64 43 54 75 88 81 97 86 113 727 Commission Decisions 14 49 55 98 73 106 699 Final Negative COMP Opinions 1 3 4 2 2 (one awaiting appeal) 15 Withdrawals 6 27 30 41 22 20 19 31 23 249 Update 22 February 2010 ©European Medicines Agency

Status of Orphan Applications 2000 Total No. of applications submitted 24 1085 Positive COMP Opinions 16 743 Commission Decisions 14 713 Final Negative COMP Opinions 15 Withdrawals 12 261 Update 22 February 2010 ©European Medicines Agency

Status of Orphan Applications 14/04/2017 Status of Orphan Applications Update 22 February 2010 ©European Medicines Agency

Distribution of Opinions 14/04/2017 Distribution of Opinions Others: 6 dermatology; 3 genitourinary; 15 hormones; 9 sensory organs; various 12 Update 22 February 2010 ©European Medicines Agency

Medicamentos Huérfanos designados en la UE (II) Abril 2000 – Febrero 2010 COMP/EMEA 8% 50% 42% Medicamentos Huérfanos designados distribuidos por tipo de población (total: 743)

Adult/Paediatric Use (designated) 14/04/2017 Adult/Paediatric Use (designated) Update 22 February 2010 ©European Medicines Agency

Adult/Paediatric Use (designated) Update 22 February 2010 ©European Medicines Agency

Prevalence Designated Conditions Update 22 February 2010 ©European Medicines Agency

Status of Orphan Marketing Authorisation Applications 14/04/2017 Status of Orphan Marketing Authorisation Applications 59 authorisations granted to date* Fabrazyme for Fabry disease Replagal for Fabry disease Glivec for chronic myeloid leukaemia, ALL, GIST, DFSP, MDS/MPD and HES/CEL Tracleer for pulmonary arterial hypertension, systemic sclerosis Trisenox for acute promyelocytic leukaemia Somavert for acromegaly Zavesca for Gaucher disease and Niemann-Pick type C disease Carbaglu for N-acetylglutamate synthetase deficiency 2 withdrawn from the register of orphan drugs cont’d Update 22 February 2010 ©European Medicines Agency

Status of Orphan Marketing Authorisation Applications 14/04/2017 Status of Orphan Marketing Authorisation Applications 59 authorisations granted to date Aldurazyme for Mucopolysaccharidosis type I Busilvex for haematopoietic progenitor cell transplantation Ventavis for pulmonary arterial hypertension Onsenal for Familial Adenomatous Polyposis Litak for indolent non-Hodgkin’s lymphoma Lysodren for adrenal cortical carcinoma Pedea for Patent Ductus Arteriosus Photobarr for Barret’s oesophagus Wilzin for Wilson's disease Xagrid for Thrombocythaemia cont’d Update 22 February 2010 ©European Medicines Agency

Status of Orphan Marketing Authorisation Applications 14/04/2017 Status of Orphan Marketing Authorisation Applications 59 authorisations granted to date Orfadin for tyrosinemia type 1 Prialt for chronic pain requiring intraspinal analgesia Xyrem for narcolepsy - withdrawn from the register of orphan drugs Revatio for pulmonary arterial hypertension Naglazyme for Mucopolysaccharidosis VI or Maroteaux-Lamy syndrome Myozyme for Glycogen Storage Disease type II (Pompe’s disease) Evoltra for acute lymphoblastic leukaemia Nexavar for renal cell carcinoma and hepatocellular carcinona cont’d Update 22 February 2010 ©European Medicines Agency

Status of Orphan Marketing Authorisation Applications 59 authorisations granted to date Sutent for gastrointestinal stromal tumour and renall cell carcinoma - withdrawn from the register of orphan drugs Savene for anthracycline extravasation Thelin pulmonary arterial hypertension Exjade for chronic iron overload requiring chelation theraphy Sprycel for chronic myeloid leukaemia and acute lymphoblastic leukaemia Inovelon for epilepsy Cystadane for homocystinuria Elaprase for mucopolysaccharidosis cont’d Update 22 February 2010 ©European Medicines Agency

Status of Orphan Marketing Authorisation Applications 59 authorisations granted to date Diacomit for myoclonic epilepsy in infancy Revlimid for multiple myeloma Soliris for paroxysmal nocturnal haemoglobinuria Siklos for sickle cell syndrome Atriance for acute lymphoblastic leukaemia Increlex for growth failure Gliolan for glioma Yondelis for soft tissue sarcoma, ovarian cancer Tasigna for chronic myelogenous leukaemia Torisel for renal cell carcinoma, mantle cell lymphoma Thalidomide Pharmion 50 mg Hard Capsules for myeloma cont’d Update 22 February 2010 ©European Medicines Agency

Status of Orphan Marketing Authorisation Applications 59 authorisations granted to date Volibris for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension Firazyr for angioedema Ceplene for acute myeloid leukaemia Kuvan for hyperphenylalaninemia Vidaza for myelodysplastic syndromes, chronic myelomonocytic leukemia and acute myeloid leukemia Nplate for thrombocytopenia Mepact for osteosarcoma Nymusa for apnoea Afinitor for renal cell carcinoma cont’d Update 22 February 2010 ©European Medicines Agency

Status of Orphan Marketing Authorisation Applications 59 authorisations granted to date Mozobil for stem cell transplantation Cayston for cystic fibrosis Arcalyst for cryopirin-associated periodic syndromes Ilaris for cryopirin-associated periodic syndromes Firdapse for Lambert-Eaton myasthenic syndrome Update 22 February 2010 ©European Medicines Agency

59 authorisations granted to date by THERAPEUTIC FIELD * Status of Orphan Marketing Authorisation Applications by Therapeutic Field 59 authorisations granted to date by THERAPEUTIC FIELD * ONCOLOGY Acute lymphoblastic leukaemia (ALL) Evoltra, Glivec, Sprycel, Atriance Acute myeloid leukaemia Trisenox, Ceplene, Vidaza Adrenal cortical carcinoma Lysodren Chronic eosinophilic leukaemia (CEL) and the hypereosinophilic syndrome (HES) Glivec Chronic myeloid leukaemia (CML) Glivec, Sprycel, Tasigna * 2 withdrawn from the register of orphan drugs cont’d Update 22 February 2010 ©European Medicines Agency

59 authorisations granted to date by THERAPEUTIC FIELD Status of Orphan Marketing Authorisation Applications by Therapeutic Field 59 authorisations granted to date by THERAPEUTIC FIELD ONCOLOGY cont’d Dermafibrosarcoma protuberans (DFSP) Glivec Dysplasia in Barrett's Esophagus Photobarr Familial Adenomatous Polyposis Onsenal Gastrointestinal stromal tumours (GIST) Glivec, Sutent withdrawn from the register of orphan drugs Glioma Gliolan cont’d Update 22 February 2010 ©European Medicines Agency

59 authorisations granted to date by THERAPEUTIC FIELD Status of Orphan Marketing Authorisation Applications by Therapeutic Field 59 authorisations granted to date by THERAPEUTIC FIELD ONCOLOGY cont’d Hairy cell leukaemia Litak Hepatocellular carcinoma Nexavar Mantle cell Lymphoma Torisel Osteosarcoma Mepact Ovarian cancer Yondelis cont’d Update 22 February 2010 ©European Medicines Agency

59 authorisations granted to date by THERAPEUTIC FIELD Status of Orphan Marketing Authorisation Applications by Therapeutic Field 59 authorisations granted to date by THERAPEUTIC FIELD ONCOLOGY cont’d Renal cell carcinoma Nexavar, Sutent withdrawn from the register of orphan drugs, Torisel, Afinitor Soft tissue sarcoma (STS) Yondelis Update 22 February 2010 ©European Medicines Agency

59 authorisations granted to date by THERAPEUTIC FIELD Status of Orphan Marketing Authorisation Applications by Therapeutic Field 59 authorisations granted to date by THERAPEUTIC FIELD ENDOCRINO/METABOLISM Acromegaly Somavert Fabry disease Fabrazyme, Replagal Gaucher disease Zavesca Glycogen Storage Disease Myozyme Growth factor-1 deficiency Increlex cont’d Update 22 February 2010 ©European Medicines Agency

59 authorisations granted to date by THERAPEUTIC FIELD Status of Orphan Marketing Authorisation Applications by Therapeutic Field - cont’d 59 authorisations granted to date by THERAPEUTIC FIELD ENDOCRINO/METABOLISM cont’d Homocystinuria Cystadane Hyperphenylalaninemia Kuvan Mucopolysaccharidosis Aldurazyme, Elaprase, Naglazyme N-acetylglutamate synthetase deficiency Carbaglu Niemann-Pick type C disease Zavesca cont’d Update 22 February 2010 ©European Medicines Agency

59 authorisations granted to date by THERAPEUTIC FIELD Tyrosinaemia Status of Orphan Marketing Authorisation Applications by Therapeutic Field 59 authorisations granted to date by THERAPEUTIC FIELD ENDOCRINO/METABOLISM cont’d Tyrosinaemia Orfadin Wilson's disease Wilzin HAEMATOLOGY Essential thrombocythaemia Xagrid Haematopoietic cell transplantation Busilvex Haemoglobinuria Soliris cont’d Update 22 February 2010 ©European Medicines Agency

59 authorisations granted to date by THERAPEUTIC FIELD Iron overload Status of Orphan Marketing Authorisation Applications by Therapeutic Field 59 authorisations granted to date by THERAPEUTIC FIELD HAEMATOLOGY cont’d Iron overload Exjade Multiple myeloma (MM) Revlimid, Thalidomide Pharmion 50 mg Hard Capsules Myelodysplastic/myeloproliferative diseases (MDS/MPD) Glivec, Vidaza Sickle cell syndrome Siklos Thrombocytopenia Nplate Stem cell transplantation Mozobil cont’d Update 22 February 2010 ©European Medicines Agency

59 authorisations granted to date by THERAPEUTIC FIELD Status of Orphan Marketing Authorisation Applications by Therapeutic Field 59 authorisations granted to date by THERAPEUTIC FIELD CARDIOVASCULAR AND RESPIRATORY Patent ductus arteriosus Pedea Pulmonary arterial hypertension (PAH) Tracleer, Ventavis, Revatio, Thelin Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension Volibris Apnoea Nymusa Cystic fibrosis Cayston cont’d Update 22 February 2010 ©European Medicines Agency

59 authorisations granted to date by THERAPEUTIC FIELD Status of Orphan Marketing Authorisation Applications by Therapeutic Field 59 authorisations granted to date by THERAPEUTIC FIELD NERVOUS SYSTEM Epilepsy Diacomit, Inovelon Narcolepsy Xyrem withdrawn from the register of orphan drugs Pain Prialt Lambert-Eaton myasthenic syndrome Firdapse cont’d Update 22 February 2010 ©European Medicines Agency

59 authorisations granted to date by THERAPEUTIC FIELD Status of Orphan Marketing Authorisation Applications by Therapeutic Field 59 authorisations granted to date by THERAPEUTIC FIELD OTHER Systemic sclerosis (scleroderma) Tracleer Anthracycline extravasations Savene Angioedema Firazyr Cryopirin-associated periodic syndromes Arcalyst, Ilaris Update 22 February 2010 ©European Medicines Agency

Status of Orphan Marketing Authorisation Applications Adopted positive opinion Tepadina for haematopoietic progenitor cell transplantation Revolade for idiopathic thrombocytopenic purpura Arzerra for chronic lymphocytic leukaemia Ongoing applications in review process 12 centralised applications in review process Variations / Line Extensions in review process Negative outcomes for orphan MAA 34 applications for MA withdrawn 6 negative decisions/refusals Update 22 February 2010 ©European Medicines Agency

Distribution of Orphan MAAs 14/04/2017 Distribution of Orphan MAAs 59 orphan authorised by centralised MA* *2 withdrawn from the register of orphan drugs Update 22 February 2010 ©European Medicines Agency

©European Medicines Agency 2010 ©European Medicines Agency 2010. 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 Update 22 February 2010 ©European Medicines Agency

Common deficiencies for ODD refusal 1) Scientific rational (Proof of Concept) weak, inconsistent or poorly justified (40%) 2) Prevalence figures based on inappropriate epidemiological data (59%) 3) Lack of medically plausible target population (artificial subsetting) (41%) 4) Inaccurate search of existing authorised methods for the orphan condition 5) Assumptions on significant benefit not credible or not well-substantiated (42%) A “dream” is not enough for designation

APPROVAL UNDER: EXCEPTIONAL CIRCUMSTANCES or CONDITIONAL APPROVAL Limited clinical data available because: rare disease (“orphan disease”) current scientific knowledge does not allow a comprehensive assessment ethical constraints in performing conventional RCT “Specific Obligations” (i.e. Clinical studies) should be carried out within an agreed timeframe Annual re-assessment of the benefit/risk ratio by the CHMP The SPC should contain this information

Some hurdles on Orphan Medicines Clinical Research (I) Lack of public awareness (“Invisible diseases”) Scarcity of Clinical Experts and Reference Centres Delays on Diagnosis (Genetic Testing / Neonatal screening) Small size population Geographic dispersion Life-threatening /chronic debilitating conditions Heterogeneous conditions Difficult to stratify by stage/severity Limited available treatments

Some hurdles on Orphan Medicines Clinical Research (II) Lack of validated biomarkers and surrogate endpoints Lack of predictive/validated preclinical models Ethical concerns on the use of placebo (e.g. Emerging therapies) and vulnerable population Off-label use (medicines for children) Participative role of patients to be increased Poorly motivated health professionals/investigators Lack of information to “care-givers” Excessive bureaucratic/administrative barriers

Challenges on Orphan Drug Clinical Development (“Feasibility Concept”) Conventional methodological designs need to be adjusted and applied in a flexible manner Alternative methodological approaches and patient-saving designs should be encouraged Compassionate and expanded access programs should not undermined the conduct of well-designed studies Investigation phase goes beyond the MA: conditional / under exceptional circumstances approval, thus early PhV planning and risk-management strategies becomes crucial « Nice to know v.s. Need to know »

Types of Clinical Studies of Orphan Drugs approved by DOPD/FDA AND EMEA* Division of Oncologic Drug Products / FDA (10 products) Centrally authorised / EMEA (22 products) * From 2nd Eurordis workshop, July 2005

List of Drugs Approved by DODP Drug (Year of Approval) Indication Number of “Pivotal” Studies Patients Clofarabine (’04) Relapsed or refractory ALL 2 66 Tositumomab (’01) CD20+ follicular NHL 5 230 Alitretinoin (’99) Kaposi sarcoma 350 Bortezomid (’03) Progressive multiple myeloma 256 Imatinib (’02) CD117+ unresectable GIST 1 147 Pemetrexed (’04) Metastatic malignant mesotheliona 448 Doxorubicin (’99) Refractory metastatic ovarian cancer 4 650 Gemtuzumab ozogamicin (’00) CD33+ acute myelocytic leukemia 3 277 Carmustine (’96) Recurrent glioblastoma multiforme 222 Alemtuzumab (’01) Chronic lymphocytic leukemia 149

Overview clinical studies in positive opinions Main (n) Phase Design Fabrazyme 1 III DB, R, Pbo, Mc Replagal 2 II DB, R, Pbo, Uc Tracleer II, III Somavert Aldurazyme Ventavis Onsenal Prialt 3 II-III Xyrem Pedea Mixed - Metaanalysis (6 studies) Photobarr Phase III Partially blinded (biopsy evaluation), R (2:1), Mc DB=double blind, R=randomised, Pbo=placebo-controlled, Mc=multicenter, Uc=unicenter Tracleer: A multicenter placebo-controlled trial (AC-052-351) including 21 patients who received bosentan 125 mg b.i.d. (11 patients receiving placebo) for 12 weeks to 28 weeks. A larger pivotal multicenter placebo-controlled trial (study AC-052-352; BREATH-1: Bosentan randomized trial of endothelin antagonist therapy for pulmonary hypertension) including 145 patients receiving bosentan at 125 mg b.i.d. (N= 74 patients) or 250 mg b.i.d. (N=70 patients), for 16 weeks to 28 weeks. Glivec-GIST: all patients received the product, no placebo or comparator

Overview clinical studies in positive opinions Main (n) Phase Design Xagrid 2 II O, NR, Mc Glivec CML Glivec GIST 3 (1x3) 1 O, NR, NC, Mc (DB), R, 2 doses, Mc Trisenox I-II, II O, NR, NC, Uc-Mc Zavesca I-II Orfadin Compassionate use O, Mc Litak Busilvex NR-not randomised, o=open

Overview clinical studies in positive opinions (I) Efficacy Patients Safety patients Fabrazyme 58 73 Replagal 41 43 Glivec CML Glivec GIST Myeloid blast crisis, n=260 Accelerated phase, n=235 Chronic phase, n=532 147 1176 Trisenox 52 251 Tracleer 246 174 Zavesca 82 96 Somavert 157 167 Carbaglu 12 20 Busilvex 102 103 Aldurazyme 45 55 Fabrazyme: The primary efficacy endpoint for the main Phase III study was reduction of the glucosphingolipid GL‑3 (which is the substrate of a-galactosidae) accumulation from the capillary endothelium of the kidney at week 20 (p<0.001). Replagal: 2 studies, 1) During the first 24 weeks (study TKT003) there was a progressive effect of agalsidase on pain resulting in a statistical trend (p=0.081) compared to placebo. In the extension phase (TKT006) placebo patients switched to active treatment and for this population a statistical significant effect could be demonstrated (p=0.0025). 2) Compared with placebo, treatment with agalsidase resulted in a reduction of cardiac GL-3 storage. (p=0.42). Glivec CML: The effectiveness of Glivec is based on overall hematologic and cytogenetic response rates measured by conventional techniques, such as bone marrow cultures and assessing metaphases for Ph+ chromosome . There are no controlled trials demonstrating a clinical benefit or increased survival. Glivec GIST: 40 PR and 40% stable disease Trisenox: Overall, 45/52 (87%), clinical CR.Despite the lack of randomised controlled studies, the CR observed with ATO in the clinical trials presented shows that Trisenox has at least similar clinical efficacy to that reported in published series with ATRA+chemotherapy in patients with relapsed disease. However, the relatively short follow-up for the ATO trials does not guarantee that long-term remission is maintained in a high proportion of patients. Tracleer: An improvement of exercise capacity (6 minute-walk test) from baseline was shown after 16 weeks increase from baseline was 36.4 meters [95% CI 24.9 meters, 47.8 meters]. A significant treatment effect as compared to placebo was shown; + 44.2 meter, some not conclusive evidence for dose-response Zavesca, out of three studies with 82 patients, 28 one with 28 was considered as the main one at the end, + 224 from HIV trials for safety Somavert: The proportion of subjects with normalized IGF-I concentrations was significantly greater for each of pegvisomant doses at each time point compared to placebo. No randomised clinical trial has been carried out versus an active treatment. Historical comparison to somatostatin analogues considered inconclusive. Carbaglu Carbamoylglutamioc acid: 12 patients treated by 10 physicians in 5 different countries out of a total of 22 patients treated in the last 25 years Aldurazyme: Two primary endpoints were selected for the pivotal study:% of predicted FVC , significant, and 6-minute walking distance, non significant trend, no clinical data on neurological manifestations of the condition. Busilvex: Demonstration of pharmacokinetic comparability, the non comparative small trials of short duration did not allow conclusions on survival or disease free survival

Overview clinical studies in positive opinions (II) Efficacy Patients Safety patients Ventavis 203 279 Xagrid* 316 (+ 242 compassionate) >4600 Onsenal 83 Litak 63 523 Photobarr 208 324 Lysodren 1064, bibliographic >2000 Pedea 429 metaanalysis 986 Wilzin 191 bibliographic 255 Ventavis: actually the indication was based on a subgroup analysis only, 95 patients, 49 treated with iloprost, + 44.7 meters in Ventavis, -7 in placebo Onsenal: For onsenal data available for safety from studies in different indications (additional data for 5617 patients), Celecoxib, 400 mg BID for 6 months, reduced the number of colorectal polyps by 28.0%, mean polyp size by 4.9% and overall polyp burden (sum of polyp diameters) by 30.7% as compared to baseline. Compared to the mean decrease of 4.5% in the placebo group, the between treatment difference was statistically significant (p=0.003). Litak (cladribin) comparable efficacy of the subcutaneous and the iv formulation Photobarr –Porfimer: Eligible patients were randomised to receive PHOTOBARR PDT plus omeprazole therapy or omeprazole Only therapy. Complete ablatio of high-grade dysplasia in roughly 60% of the Photobarr group compared to 15% in the omeprazole group. Lysodren: In terms of overall survival, four studies conclude that mitotane treatment does not increase the survival rate whereas five find an increase in the survival rate. Some studies provide accurate information on tumour regression or disappearance and demonstrate that the threshold of 14 mg/l appears necessary to induce an objective tumour regression Pedea: From the 6 studies used in the metaanalysis only one compared indomethacin with Pedea (trometamol, sodiumchloride) the others compared indomethacin with ibuprofen-lysine. Pedea had similar efficacy to Indomethacin. The applicant's dose ranging study is limited and inadequate when taken on its own. However, when combined with the more impressive published data, the dose ranging study is consistent with the earlier studies and supports the choice of dose. Based on the results from the dose-response study of Pedea in 40 preterm newborn infants, it is considered that sufficient information on efficacy in infants of 24-26 weeks of gestational age has not yet been provided. The ductus arteriosus closure rate associated to the 10-5-5 mg/kg dose regimen was 75% (6/8) in neonates of 27-29 weeks’ gestation and 33% (2/6) in neonates of 24-26 weeks’ gestation. A warning has therefore been introduced in Section 4.3 of the Summary of Product Characteristics, stating that in preterm newborn infants less than 27 weeks of gestational age, the closure rate of the ductus arteriosus was shown to be low at the recommended dose regimen.

Exposure (5/10,000 = 227,500 patients in EU)* 0.00125  50 12 Carbaglu 0.6  22,600 157 Somavert 0.06  2,200 147 Gilvec (GIST)  22,600 (*1060) 92 Zavesca 0.95  36,000 246 Tracleer 0.8  30,000 52 Trisenox 0.9  34,000 1027 Glivec (CML) 0.13-0.27  5,000-10,000 41 Replagal 58 Fabrazyme Prev Population affected (000 EU) Efficacy Patients

BE AWARE OF... Randomised clinical trials are the gold standard for investigating and confirming clinical safety and efficacy of new medicinal products ... but ... the evidence indicates that the benefit/risk profile is driving the orphan drug approval when there are difficulties to perform conventional prospective randomised trials (Some) rare conditions may need alternative methodological and statistical considerations without compromising efficacy and/or undermining safety EMEA guideline for the conduct of clinical investigations in small sized populations (adopted, February 2006)

The patient’s perspective: Why collaborate in clinical trials? Sponsors Research Market Clinical trials Disease Treatments Experts Actors Users Patients

When to collaborate in clinical trials? Discussion of results Protocole On-going Conclusions Constructive Collaboration Criticism Agreement «It is desirable» «It is possible» «It is stimulating»

Industry Clinical Researcher The increasing complex environment of clinicians Regulatory Authorities Funding Research Bodies Industry ERC Primary Care General Hospitals Teaching Hospitals Individuals Families Clinical Researcher Patients Organization Supportive Team NHS Pharmaceutical Policy Learned Societies Academic Liaisons Ethical Care Bodies ERC: Ethic Review Committees

Rare Diseases’ Action Lines (I) TRAINING CONTINUING PROFESSIONAL DEVELOPMENT BIOMEDICAL EPIDEMIOLOGICAL RESEARCH Public-private Partenariat Pharmaceutical Industry QUALITATIVE AND SOCIAL RESEARCH Professionals patients INFORMATION

Rare Diseases’ Action Lines (II) REFERENCE CENTERS EXPERTISE/SPECIALIZED HOSPITALS HEALTH AND SOCIAL SERVICES PATIENTS’ MOBILITY Experts’ Network Fostering Social Care PRIMARY CARE/ HOME HELP DEPENDENCY AND DISABILITY

Rare Diseases’ Action Lines (III) FAMILY SUPPORT AND SPECIAL EDUCATION HEALTH INTERVENTIONS/ GENETIC DIAGNOSE Timely and equity access Promoting Autonomy THERAPEUTIC INTERVENTIONS WORK FACILITIES AND LABOR ENVIRONMENT

Rare Diseases’ Action Lines (IV) EU Advisory Agency OEER BEST PRACTICES EU CONFERENCES EU BUDGET Health Indicators NATIONAL BUDGETS EU/National and Regional Co-ordination RESEARCH, TRAINING, EXPERTS

DOCUMENTOS DE REFERENCIA Comunicación de la Comisión Europea (GD Sanco, 2008): Las enfermedades raras: un desafío para Europa. Comisión Europea Recomendación del Consejo, 2009 Senado: Ponencia de Estudio de ER, 23 febrero 2007 Plan Nacional de Enfermedades Raras 20 junio 2009 Plan Nacional Francés de ER 2004-2008

Recent Spanish contribution to foster Orphan Drug Research for Rare Diseases (I) Priority for pricing and reimbursement (Dirección General de Farmacia) New decree for compassionate and extended use (AEMPS) Scientific Advice for Clinical Investigations (AEMPS) CIBER for Rare Diseases Research (Instituto de Salud Carlos III) Burgos National Center (Ministerio de Asuntos Sociales) Decree for establishing references centers (Ministerio de Sanidad) Call for funding independent clinical research (January 2007/20ME, DGF/AEMPS) Report and recommendations from the Spanish Senate (February 2007) Priority for several Spanish-based pharmaceutical industries (Farmaindustria / Plan Profarma, Ministerio de Industria) Disabilities and Social Help (Ley de Dependencia)

Recent Spanish contribution to foster Orphan Drug Research for Rare Diseases (II) National Health Care System: Plan Nacional de Enfermedades Raras (June 2009) Several actions at autonomous and regional level: Cataluña Propuesta de resolución sobre enfermedades raras; Parlamento de Cataluña. Tram 250/01182-08; Butlletí Oficial del Parlament de Catalunya; 31 julio 2008; Núm. 312; Generalitat de Catalunya; creación de la Comisión Asesora en Enfermedades Raras (CAMM) (mayo 2009) La Marató de TV3 año 2009 Enfermedades Raras Generalitat de Catalunya; creación de la Comisión de Acceso a Terapias Complejas (CATFAC) (febrero 2010)

….But …… Benefits of EU Orphan Medicines Regulation Awareness activities growing Positive impact on SME’s Increasing innovative medicines: paving the road for the entrance of emerging therapies Facilitating liaison of reference health/research centres Openness of Public Clinical Trials Database Better understanding of patient’s needs Progressive prioritisation of RD on public health agendas ….But ……

…….Much still remains to be done……… Ensuring availability/access to OMP for all patients Warranting affordability and long-term sustainability Global approach and more inter-regional cross-collaboration Better epidemiological knowledge of many rare conditions Developing appropriate methodological / statistical patient-saving approaches Strengthen early pharmacovigilance planning and risk management strategies Increasing public funding from UE/national institutions More and better co-ordination of National Incentives

So….. Rare Diseases offers….. An unique and challenging clinical paradigm Encompasses a wide range of different medical conditions Knowledge gather in this setting can be extrapolated in other conventional diseases High contribution from patients organisations Stimulates creativity and interest of clinicians and academics Big-pharma and SMEs may use this opportunity to further develop “personalised” medicines

Creating a true EU partnering environment with all stake-holders Rare (low-prevalence) diseases are a pan-European challenge that need national solutions …also… Rare conditions are a national problem that need EU strong support and policy commitment