Presentation is loading. Please wait.

Presentation is loading. Please wait.

1 Rare Diseases and Orphan Medicinal Products Máster en diagnóstico y terapia de las enfermedades raras Josep Torrent-Farnell Universitat Autònoma de Barcelona.

Similar presentations


Presentation on theme: "1 Rare Diseases and Orphan Medicinal Products Máster en diagnóstico y terapia de las enfermedades raras Josep Torrent-Farnell Universitat Autònoma de Barcelona."— Presentation transcript:

1 1 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

2 2 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)

3 3 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: million Spain:3,5 million (*) Estimate figures

4 4 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

5 5 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 (III)

6 6 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. invisibleunknown 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). Some facts on rare diseases (IV)

7 7 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.

8 8 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 * NORD, EURORDIS, ORPHANET, databases ELA Pompe Disease Nieman-Pick-Disease Gaucher Disease Fabry Disease Polyarteritis Nodosa Mucopolysaccharidosis Thalasemias Ewing Sarcoma Churg-Strauss Syndrome

9 9 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

10 10 Unmet medical needs for patients affected by rare disorders require global and international joint efforts

11 11 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

12 12 Orphan Medicinal Products in the EU International Comparison

13 13 Comparative Requirements for ODD USEU Epidemiological “prevalence” Nature of disease 6.8 / 10,000 Rare 5 / 10,000 Life-threatening, debilitating Scientific rationaleYES Economic (lack of ROI)YES Significant benefit (added therapeutic value) “Medically plausible” subset Time of application Medical devices NO YES Before MA Humanitarian use YES Before MA NO

14 14 Comparative Requirements for ODD USEU Market exclusivity (yrs)710 MA fee–waiverYES Protocol assistance/ scientific advice YES Direct grants from regulatory agency YES (Clinical studies)NO Other public grantsYES (NIH)YES (DG Research, National) Tax creditsYES (50% of clinical cost)Depends on MS

15 15 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

16 16 Orphan Medicinal Products: Designation vs. Authorization (I) Authorization –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

17 17 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)

18 18 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 (I): Designation

19 19 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 Some basic considerations (II): Marketing authorizations

20 20 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

21 21 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)

22 22 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

23 23 EMEA COMP EU Panel Experts rare diseases CHMP Marketing Authorisation ‘Entry Level’‘Outcome’ Review Applications Designation Advice on designationProtocol AssistanceScientific Advice Review Applications

24 24 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 Orphan Designation Criteria

25 25 Comparative US/EU Criterion for Orphan Drug Designation Common Epidemiological (prevalence) (7/ 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

26 26 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)

27 27 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

28 28 Orphan Medicinal Products in the EU Period of ten years exclusivity from the date of marketing Conditions orphan designation authorisation throughout EU AND marketing authorisation throughout EU Scope of exclusivity similar medicinal products same indication(s) no market authorisation for similar medicinal products in the same indication(s)

29 29 From: REGULATION (EC) No 141/2000 Article 8, Market exclusivity accept another applicationgrant a marketing authorisation extend an existing marketing authorisation Where a marketing authorisation in respect of an orphan medicinal product is granted pursuant to Regulation (EEC) No 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.

30 30 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

31 31 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

32 32 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

33 33 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”)

34 34 Subsetting a medical condition:“salami-slicing strategy” Total >5/ “Subset” <5/ Prevalence criteria NoYes

35 35 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

36 36 Medically Plausible Subsets (II) 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 ? Questions to address:

37 37 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

38 38 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

39 39 Protocol assistance 3 Representatives of the COMP are members of the Scientific Advice Review Group since January 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

40 40 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

41 41 Proposed Orphan condition Prevalence justification < 5/ No Yes Satisfactory methods YesNo Negative opinion Overall Rationale Designation Assumption on Significant benefit NoYes NoYes Medical Plausibility YesNo Redefine

42 42 SUMMARY OF ORPHAN DRUGS

43 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 Febrero 2010)

44 Update 22 February 2010 ©European Medicines Agency Status of Orphan Applications Total No. of applications submitted Positive COMP Opinions Commission Decisions Final Negative COMP Opinions (one awaiting appeal) 15 Withdrawals

45 Update 22 February 2010 ©European Medicines Agency Status of Orphan Applications 2000Total No. of applications submitted Positive COMP Opinions Commission Decisions Final Negative COMP Opinions 015 Withdrawals 12261

46 Update 22 February 2010 ©European Medicines Agency Status of Orphan Applications

47 Update 22 February 2010 ©European Medicines Agency Distribution of Opinions

48 8% 50% 42% 8% 50% 42% Medicamentos Huérfanos designados distribuidos por tipo de población (total: 743) Medicamentos Huérfanos designados distribuidos por tipo de población (total: 743) Medicamentos Huérfanos designados en la UE (II) Abril 2000 – Febrero 2010 COMP/EMEA

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

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

51 Update 22 February 2010 ©European Medicines Agency Prevalence Designated Conditions

52 Update 22 February 2010 ©European Medicines Agency  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 drugs2 withdrawn from the register of orphan drugs H 59 authorisations granted to date* cont’d Status of Orphan Marketing Authorisation Applications

53 Update 22 February 2010 ©European Medicines Agency  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 H 59 authorisations granted to date cont’d Status of Orphan Marketing Authorisation Applications

54 Update 22 February 2010 ©European Medicines Agency  Orfadin for tyrosinemia type 1  Prialt for chronic pain requiring intraspinal analgesia withdrawn from the register of orphan drugs  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 Status of Orphan Marketing Authorisation Applications H 59 authorisations granted to date cont’d

55 Update 22 February 2010 ©European Medicines Agency withdrawn from the register of orphan drugs  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 Status of Orphan Marketing Authorisation Applications H 59 authorisations granted to date cont’d

56 Update 22 February 2010 ©European Medicines Agency  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 Status of Orphan Marketing Authorisation Applications H 59 authorisations granted to date cont’d

57 Update 22 February 2010 ©European Medicines Agency  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 Status of Orphan Marketing Authorisation Applications H 59 authorisations granted to date cont’d

58 Update 22 February 2010 ©European Medicines Agency  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 H 59 authorisations granted to date Status of Orphan Marketing Authorisation Applications

59 Update 22 February 2010 ©European Medicines Agency H 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) * 2 withdrawn from the register of orphan drugs Glivec, Sprycel, Tasigna * 2 withdrawn from the register of orphan drugs Status of Orphan Marketing Authorisation Applications by Therapeutic Field cont’d

60 Update 22 February 2010 ©European Medicines Agency H59 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) withdrawn from the register of orphan drugs Glivec, Sutent withdrawn from the register of orphan drugs  Glioma Gliolan Status of Orphan Marketing Authorisation Applications by Therapeutic Field cont’d

61 Update 22 February 2010 ©European Medicines Agency H59 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 Status of Orphan Marketing Authorisation Applications by Therapeutic Field cont’d

62 Update 22 February 2010 ©European Medicines Agency H59 authorisations granted to date by THERAPEUTIC FIELD ONCOLOGY cont’d  Renal cell carcinoma withdrawn from the register of orphan drugs Nexavar, Sutent withdrawn from the register of orphan drugs, Torisel, Afinitor  Soft tissue sarcoma (STS) Yondelis Status of Orphan Marketing Authorisation Applications by Therapeutic Field

63 Update 22 February 2010 ©European Medicines Agency Status of Orphan Marketing Authorisation Applications by Therapeutic Field H59 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

64 Update 22 February 2010 ©European Medicines Agency Status of Orphan Marketing Authorisation Applications by Therapeutic Field - cont’d H59 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

65 Update 22 February 2010 ©European Medicines Agency Status of Orphan Marketing Authorisation Applications by Therapeutic Field H59 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

66 Update 22 February 2010 ©European Medicines Agency Status of Orphan Marketing Authorisation Applications by Therapeutic Field H59 authorisations granted to date by THERAPEUTIC FIELD âHAEMATOLOGY 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

67 Update 22 February 2010 ©European Medicines Agency H59 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 Status of Orphan Marketing Authorisation Applications by Therapeutic Field cont’d

68 Update 22 February 2010 ©European Medicines Agency H59 authorisations granted to date by THERAPEUTIC FIELD NERVOUS SYSTEM  Epilepsy Diacomit, Inovelon  Narcolepsy withdrawn from the register of orphan drugs Xyrem withdrawn from the register of orphan drugs  Pain Prialt  Lambert-Eaton myasthenic syndrome Firdapse Status of Orphan Marketing Authorisation Applications by Therapeutic Field cont’d

69 Update 22 February 2010 ©European Medicines Agency Status of Orphan Marketing Authorisation Applications by Therapeutic Field H59 authorisations granted to date by THERAPEUTIC FIELD OTHER  Systemic sclerosis (scleroderma) Tracleer  Anthracycline extravasations Savene  Angioedema Firazyr  Cryopirin-associated periodic syndromes Arcalyst, Ilaris

70 Update 22 February 2010 ©European Medicines Agency  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 Status of Orphan Marketing Authorisation Applications

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

72 Update 22 February 2010 ©European Medicines Agency ©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: opyritel.htm opyritel.htm

73 73 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

74 74 APPROVAL UNDER: EXCEPTIONAL CIRCUMSTANCES or CONDITIONAL APPROVAL H H Limited clinical data available because: H rare disease (“orphan disease”) H current scientific knowledge does not allow a comprehensive assessment H ethical constraints in performing conventional RCT H “Specific Obligations” (i.e. Clinical studies) should be carried out within an agreed timeframe H Annual re-assessment of the benefit/risk ratio by the CHMP H The SPC should contain this information

75 75 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

76 76 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 Some hurdles on Orphan Medicines Clinical Research (II)

77 77 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 »

78 78 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

79 79 List of Drugs Approved by DODP Drug (Year of Approval) IndicationNumber of “Pivotal” Studies Patients Clofarabine (’04)Relapsed or refractory ALL266 Tositumomab (’01)CD20+ follicular NHL5230 Alitretinoin (’99)Kaposi sarcoma2350 Bortezomid (’03)Progressive multiple myeloma2256 Imatinib (’02)CD117+ unresectable GIST1147 Pemetrexed (’04)Metastatic malignant mesotheliona1448 Doxorubicin (’99)Refractory metastatic ovarian cancer4650 Gemtuzumab ozogamicin (’00) CD33+ acute myelocytic leukemia3277 Carmustine (’96)Recurrent glioblastoma multiforme1222 Alemtuzumab (’01)Chronic lymphocytic leukemia3149

80 80 Overview clinical studies in positive opinions Main (n)PhaseDesign Fabrazyme1IIIDB, R, Pbo, Mc Replagal2IIDB, R, Pbo, Uc Tracleer2II, IIIDB, R, Pbo, Mc Somavert1IIIDB, R, Pbo, Mc Aldurazyme1IIIDB, R, Pbo, Mc Ventavis1IIIDB, R, Pbo, Mc Onsenal1IIDB, R, Pbo, Mc Prialt3II-IIIDB, R, Pbo, Mc Xyrem2IIIDB, R, Pbo, Mc PedeaMixed-Metaanalysis (6 studies) Photobarr1Phase IIIPartially blinded (biopsy evaluation), R (2:1), Mc

81 81 Main (n)PhaseDesign Xagrid2IIO, NR, Mc Glivec CML Glivec GIST 3 (1x3) 1 II O, NR, NC, Mc (DB), R, 2 doses, Mc Trisenox2I-II, IIO, NR, NC, Uc-Mc Zavesca1I-IIO, NR, NC, Mc Orfadin1Compassio nate use O, Mc Litak1IIO, NR, Mc Busilvex2IIO, NR, NC, Mc Overview clinical studies in positive opinions

82 82 Overview clinical studies in positive opinions (I) Efficacy PatientsSafety patients Fabrazyme5873 Replagal4143 Glivec CML Glivec GIST Myeloid blast crisis, n=260 Accelerated phase, n=235 Chronic phase, n= Trisenox52251 Tracleer Zavesca8296 Somavert Carbaglu1220 Busilvex Aldurazyme4555

83 83 Efficacy PatientsSafety patients Ventavis Xagrid*316 (+ 242 compassionate) >4600 Onsenal83 Litak63523 Photobarr Lysodren1064, bibliographic>2000 Pedea429 metaanalysis986 Wilzin191 bibliographic255 Overview clinical studies in positive opinions (II)

84 84 Exposure (5/10,000 = 227,500 patients in EU)*  50 12Carbaglu 0.6  22, Somavert 0.06  2, Gilvec (GIST) 0.6  22,600 (*1060) 92Zavesca 0.95  36, Tracleer 0.8  30,000 52Trisenox 0.9  34, Glivec (CML)  5,000-10,000 41Replagal  5,000-10,000 58Fabrazyme PrevPopulation affected (000 EU) Efficacy Patients

85 85 BE AWARE OF the evidence indicates that the benefit/risk profile is driving the orphan drug approval when there are difficulties to perform conventional prospective randomised trials Randomised clinical trials are the gold standard for investigating and confirming clinical safety and efficacy of new medicinal products... but (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)

86 86 Patients The patient’s perspective: Why collaborate in clinical trials? Clinical trials DiseaseTreatments ExpertsActors Users Research Market Sponsors

87 87 When to collaborate in clinical trials? ProtocoleOn-going Discussion of results Constructive Collaboration Criticism Agreement «It is possible» «It is stimulating» «It is desirable» Conclusions

88 88 Clinical Researcher Individuals Families Patients Organization Learned Societies Supportive Team NHS Pharmaceutical Policy Industry Regulatory Authorities Primary Care General Hospitals Teaching Hospitals Academic Liaisons ERC The increasing complex environment of clinicians Funding Research Bodies Ethical Care Bodies ERC: Ethic Review Committees

89 89 TRAINING CONTINUING PROFESSIONAL DEVELOPMENT Professionals patients INFORMATION BIOMEDICAL EPIDEMIOLOGICAL RESEARCH Public-private Partenariat Pharmaceutical Industry QUALITATIVE AND SOCIAL RESEARCH Rare Diseases’ Action Lines (I)

90 90 REFERENCE CENTERS EXPERTISE/SPECIALIZED HOSPITALS Experts’ Network PRIMARY CARE/ HOME HELP HEALTH AND SOCIAL SERVICES PATIENTS’ MOBILITY Fostering Social Care DEPENDENCY AND DISABILITY Rare Diseases’ Action Lines (II)

91 91 HEALTH INTERVENTIONS/ GENETIC DIAGNOSE Timely and equity access THERAPEUTIC INTERVENTIONS FAMILY SUPPORT AND SPECIAL EDUCATION Promoting Autonomy WORK FACILITIES AND LABOR ENVIRONMENT Rare Diseases’ Action Lines (III)

92 92 EU Advisory Agency OEER EU/National and Regional Co-ordination RESEARCH, TRAINING, EXPERTS BEST PRACTICES EU CONFERENCES EU BUDGET Health Indicators NATIONAL BUDGETS Rare Diseases’ Action Lines (IV)

93 93 DOCUMENTOS DE REFERENCIA Las enfermedades raras: un desafío para EuropaComunicación de la Comisión Europea (GD Sanco, 2008): Las enfermedades raras: un desafío para Europa. Comisión Europea Recomendación del Consejo, 2009Recomendación del Consejo, 2009 Senado: Ponencia de Estudio de ER, 23 febrero 2007Senado: Ponencia de Estudio de ER, 23 febrero 2007 Plan Nacional de Enfermedades Raras20 junio 2009Plan Nacional de Enfermedades Raras 20 junio 2009 Plan Nacional Francés de ER

94 94 Recent Spanish contribution to foster Orphan Drug Research for Rare Diseases (I) 1.Priority for pricing and reimbursement (Dirección General de Farmacia) 2.New decree for compassionate and extended use (AEMPS) 3.Scientific Advice for Clinical Investigations (AEMPS) 4.CIBER for Rare Diseases Research (Instituto de Salud Carlos III) 5.Burgos National Center (Ministerio de Asuntos Sociales) 6.Decree for establishing references centers (Ministerio de Sanidad) 7.Call for funding independent clinical research (January 2007/20ME, DGF/AEMPS) 8.Report and recommendations from the Spanish Senate (February 2007) 9.Priority for several Spanish-based pharmaceutical industries (Farmaindustria / Plan Profarma, Ministerio de Industria) 10.Disabilities and Social Help (Ley de Dependencia)

95 95 Recent Spanish contribution to foster Orphan Drug Research for Rare Diseases (II) 11.National Health Care System: Plan Nacional de Enfermedades Raras (June 2009) 11.Several actions at autonomous and regional level: Cataluña –Propuesta de resolución sobre enfermedades raras; Parlamento de Cataluña. Tram 250/ ; 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)

96 96  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 …… Benefits of EU Orphan Medicines Regulation

97 97 …….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

98 98 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

99 99 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


Download ppt "1 Rare Diseases and Orphan Medicinal Products Máster en diagnóstico y terapia de las enfermedades raras Josep Torrent-Farnell Universitat Autònoma de Barcelona."

Similar presentations


Ads by Google