2009 Convegno Malattie Rare Schieppati [22 01]

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Oggi possiamo curare meglio le malattie rare ?

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2009 Convegno Malattie Rare Schieppati [22 01]

  1. 1. Oggi possiamo curare meglio le malattie rare ? Arrigo Schieppati 1
  2. 2. Rare diseases: the facts 5000-8000 rare diseases Prevalence in EU <5/10,000 About 6-8% of the EU population (30 million) have a RD 2
  3. 3. Rare diseases: the facts >50% are pediatric >85% are serious/life-threatening Chronic No effective treatment available Heterogeneous Very vulnerable, underserved populations
  4. 4. JM Walshe BMJ 1975 4
  5. 5. US Orphan Drug Act - 1983 Tax incentives Exclusive or modified patent protection Priority Review Grants from FDA Amendments to antitrust laws to permit limited exchange of data, pooling of resources, other collaborative efforts Government purchase of orphan drugs 6
  6. 6. A long way to Orphan Drug Regulation in the EU 1993 Rare diseases a priority for healthcare area in EU 1994 “Towards an orphan drug policy in EU” Aug ‘96 1st draft of Regulation on Orphan Medicinal Products July ‘98 7th draft approved by EU Commission Sept ‘98 EU Parliament (EP) receives Proposal Dec ‘99 Regulation (EC) 141/2000 on Orphan Medicinal Product approved 7
  7. 7. Underlying Principles Prevalence Article 3.1.a: introduces two alternative tests for designation of OMPs Prevalence criteria: Disease affecting no more than 5/10,000 persons in the EU Profitability criteria: Need for incentives to justify the investment 8 A. Rappagliosi
  8. 8. Underlying Principles Equity « Patients suffering from rare conditions should be entitled to the same quality of treatment as other patients. » Investment « Promising drugs to treat these conditions would not be developed unless specific measures are taken to stimulate research and development of orphan drugs» 9 A. Rappagliosi
  9. 9. Underlying Principles Access « The purpose of this regulation is…. to provide incentives for the research, development and placing on the market, of designated OMPs. » « Medicinal products designated as orphan shall be eligible for incentives made available to support research into, and the development and availability of, orphan medicinal products…» A. Rappagliosi 10
  10. 10. Orphan Drug in Europe: Before 2000 ORPHAN DRUGS AVAILABLE: 12 • alemtuzumab • imiglucerase • alitretinoin • mercaptimine • deferiprone • phenylbutyrate • factor VII A • protein C • factor IX • riluzole • factor IX • temozolomide 11 Joppi, Bertelè, Garattini B J Clin Pharm 2006
  11. 11. EMEA: Orphan drug designation and marketing 550 536 500 463 450 400 365 350 292 300 250 212 200 145 150 96 100 58 47 42 50 30 22 18 12 7 3 0 2001 2002 2003 2004 2005 2006 2007 2008 designation marketing
  12. 12. Orphan Drug in Europe: 2000-2008 ORPHAN DRUG DESIGNATIONS 536 ORPHAN DRUGS APPROVED 47 8% 13
  13. 13. FDA: Orphan drug designation and marketing Orphan drug designation and marketing (N) 1951 2000 1500 1000 500 325 0 1983 2008 83 designation marketing
  14. 14. Orphan Drug in USA : 1983 - 2008 ORPHAN DRUG DESIGNATIONS 1951 ORPHAN DRUGS APPROVED 325 16.6 % 15
  15. 15. Orphan Drug in Europe: 2000-2004 ORPHAN DRUG DESIGNATIONS 23 DRUGS APPROVED UNDER EXCEPTIONAL CIRCUMSTANCES 12 51% 16 Joppi, Bertelè, Garattini B J Clin Pharm 2006
  16. 16. Under exceptional circumstances The indications is intended for condition so rarely that cannot reasonably be expected to gain comprehensive evidence In the present state of scientific knowledge, comprehensive information cannot be provided it would be contrary to generally accepted principles of medical ethics to collect such information 17
  17. 17. Under exceptional circumstances Marketing authorisation may be granted on the following conditions: Complete the studies and reassess risk/benefit profile Drug dispensation only through hospitals Patients and doctors well informed about the limited evidence of efficacy 18
  18. 18. Drug Disease Prevalence N. Pts Algasidase Fabry 0.25 41 Anagrelide Essential 2-3 1446 throbocytemia Arsenic trioxyde APML NA 52 Bosentan Pulm Hypert0.005 32 Carglumic ac, NAG synth def 0.000125 20 Celecoxib Fam. Polyposis 0.3 970 Cladribine Hairy Cell L NA 120 Ibuprofen Patent ductus NA 131 Iloprost Pulm Hypert0.005 203 Imatinib CML 0.18 1225 Laronidase MPS1 0.025 45 Migulstat Gaucher 0.33 28 Mitotane Adrenal CA 0.1 500 Pegvisomant Acromegaly 0.5 112 Porfimer Na Barrett’s esop 2.3 208 Zync acet. Wilson 0.6 148 19
  19. 19. Orphan Drugs for the same indication: no comparative studies α β • ALGASIDASE-α/ ALGASIDASE-β FABRY DISEASE • MIGLUSTAT / IMIGLUCERASE GAUCHER • ARSENIC TRIOXIDE / RETINOIC ACID PROMYELOCITIC LEUKEMIA • BOSENTAN / ILOPROST / PULMONARY • SILDENAFIL / HYPERTENSION • IBUPROFEN / INDOMETHACIN PATENT DUCTUS ARTERIOSUS • CLADRIBINE / IFN-ALPHA HAIRY LEUKEMIA • ZICOTINIDINE / MORPHINE INTRATHECAL ANALGESIA 20 Joppi, Bertelè, Garattini B J Clin Pharm 2006
  20. 20. Major problems with Orphan Drug approval LACK OF DOSE FINDING LACK OF PHASE 3 TRIALS SURROGATE END-POINTS SHORT DURATION OF TREATMENT SMALL NUMBER OF PATIENTS POOR KNOWLEDGE OF ADVERSE REACTIONS 21 Joppi, Bertelè, Garattini B J Clin Pharm 2006
  21. 21. It is certainly difficult to find a balance between the urgent need for drugs for patients with rare diseases while guaranteeing at least their quality, efficacy and safety and, when necessary, making comparisons with existing drugs Probably the lack of reliable methods for evaluating the effect of drugs on small numbers of patients is partly responsible for the general poor quality of the dossiers. Joppi, Bertelè, Garattini B J Clin Pharm 2006 22
  22. 22. Itraconazole to Prevent Fungal Infections in Chronic Granulomatous Disease John I. Gallin, M.D., et al. 2003 Thirty-nine patients with chronic granulomatous disease were enrolled in the study. Accrual lasted from October 1991 to March 2000.
  23. 23. There are orphan diseases that are difficult to study because they don't have biological markers. For example, neurological diseases: you cannot get a brain biopsy to prove that an experimental treatment has changed brain chemistry, or prevented further neurodegeneration. For many disorders how do you prove quot;preventionquot;, or quot;delay of progressionquot; in a six- month or one-year clinical trial for a chronic disease that has slowly evolving symptoms?
  24. 24. CONTROLLED TRIALS IN RARE DISEASES: HOW MANY? HOW INFORMATIVE? ADEQUATE? Annalisa Perna, Giovanni Antonio Giuliano, Arrigo Schieppati, Marco Costantini, Mariya Ganeva, Erica Daina, Rumen Stevanov, Giuseppe Remuzzi Istituto di Ricerche Farmacologiche ‘Mario Negri’ Centro di Ricerche Cliniche per le Malattie Rare ‘Aldo e Cele Daccò’ Society for Clinical Trials, 28th Meeting , Montreal 2007
  25. 25. QUALITY OF PUBLISHED RCT IN RARE DISEASES Diseases classified as rare, available in the database of the Information Center for Rare Diseases (ICRD), IRFMN The first 50 diseases, sorted by the number of contacts at May 23, 2003 Identification of Randomized Clinical Trials (RCT) in MEDLINE was done, according to the recommended Cochrane search strategy for retrieval of reports of controlled trials Robinson KA., Int J Epidemiol, 2002
  26. 26. Excluded (1) Rare diseases selected (50) (No interesting title) Rare diseases with potentially interesting abstract Excluded (22) reviewed (49) (non randomized or reviews) Rare diseases with at least one RCT Excluded (7) identified (27) (cross-over: 2) (other reasons: 3) (cross-over + other reasons: 2) Rare diseases with at least one eligible RCT Excluded (2) identified (20) (not found) Rare diseases with at least one eligible RCT evaluated (18)
  27. 27. Titles identified through the bibliographic Excluded (6,384) search (7,410) (No interesting title: 6,252) (No abstract available: 132) Potentially interesting Excluded (855) abstracts reviewed (1,026) (Non randomized or reviews) Abstracts with an RCT identified (171) Excluded (64) (Cross-over: 37) (Different disease: 12) (Other reasons: 15) Potentially appropriate RCTs (107) Excluded (28) (Full article not available) RCTs included (79)
  28. 28. 80 % 60 51 % 45 % 40 20 4% 0 No difference In favour of In favour of EXPERIMENT STANDARD AL treatment treatment
  29. 29. 80 74 % % 60 40 26 % 20 0 Surrogate Survival endpoints
  30. 30. QUALITY OF PUBLISHED RCT IN RARE DISEASES Weak points found - Power calculations - Interim analyses/early stopping rules - Recruitment period definition - No. of assessable patients at study end - Clear report of primary and secondary outcome - Choice of important clinical endpoints - External validity of study findings
  31. 31. QUALITY OF PUBLISHED RCT IN RARE DISEASES Whenever feasible, RCTs in rare diseases should be performed with the highest standards. Weak points found in RCTs on common diseases become issues of great concern in rare diseases Lagakos SW., N Engl J Med, 2003 When applicable, novel approaches should be better implemented, particularly when focused on saving the number of patients enrolled Halpern SD et al.. JAMA, 2002
  32. 32. European Clinical Research Infrastructures Network www.ecrin.org
  33. 33. Finland FinnCRIN Sweden SweCRIN Denmark Ireland DCRIN ICRIN UK EORTC UKCRN Germany KKS EFGCP Austria ATCRIN France Inserm Hungary Switzerland HECRIN SCRN Spain Italy SCReN IRFMN & CIRM National networks of Clinical Research Centres / Clinical Trial Units 34
  34. 34. Challenges to clinical research in Europe Main bottlenecks : Access to patients: fragmentation of health systems Cost: fragmentation of public funding Quality of infrastructures
  35. 35. ECRIN, an integrated infrastructure for clinical trials in the EU ECRIN-1 (2004-2005) : Identifying bottlenecks ECRIN-2 (2006-2008) : Design of the infrastructure ECRIN-3 (2008 -> ) : ESFRI roadmap Preparation, construction and operation of the infrastructure supporting multinational clinical trials in the EU In line with expectations of FP7 ‘Innovative Medicines Initiative’
  36. 36. Gaucher’s disease 2001 1991 Imiglucerase
  37. 37. One year treatment with imiglucerase: 400.000$ 38
  38. 38. 39 FBignami: 6th ERTC workshop Barcelona ona - 9 July 2007
  39. 39. 40 FBignami: 6th ERTC workshop Barcelona ona - 9 July 2007
  40. 40. 41 FBignami: 6th ERTC workshop Barcelona ona - 9 July 2007
  41. 41. Time to availability of OMPs
  42. 42. Time to availability of OMPs
  43. 43. In Italy OD with market autorization in EU 44 Available in Italy 27 Days before MA in Italy 437 Range 106-1004 Source of Data: ISS web page. Data at March 31, 2008 44
  44. 44. OMP price in EU
  45. 45. Countries with a small population suffer from a longer delay in availability of OMPs In some countries with high GDP there are only a small number of OMPs really available This situation is also a result of commercial strategies, but patients cannot accept it and it is against the legislation. 47 FBignami: 6th ERTC workshop Barcelona ona - 9 July 2007
  46. 46. Positive Outcomes of the Orphan Drug legislation Building biotech science Growth of large and small pharmaceutical firms Support to the economy Development of cutting-edge technology
  47. 47. Trends in Orphan Product Development Targeted therapies Recombinant therapies Monoclonal antibody therapies Gene therapy
  48. 48. Problems Encountered Cost + Access Loss of some orphan drugs Drug prices Access remains an issue
  49. 49. And So… Orphan Products Development in the US and EU has proved beneficial for Patients Families Industry Economy
  50. 50. PRESCRIZIONE OFF-LABEL 1. assunzione di responsabilità da parte del medico prescrittore prescrizione off-label per il paziente non può essere utilmente trattato Malattia con medicinali autorizzati Rara = l’impiego del medicinale proposto è sostenuto prescrizione da studi clinici almeno di fase II off-label per [Legge Finanziaria 2008] Malattia NON Rara 2. consenso informato da parte del paziente 3. I farmaci possono essere rimborsati solo se: prescritti da un medico che opera presso un Presidio della Rete MR prescritti per mezzo dell’apposito PT
  51. 51. ACCESSO AI FARMACI Ai pazienti affetti dalle malattie rare di cui al D.M. 18 maggio 2001, N. 279 possono essere forniti gratuitamente: 1. tutti i farmaci registrati sul territorio nazionale, di classe A (compresi quelli di fascia H) e C 2. i farmaci inseriti nello specifico elenco AIFA ai sensi della legge 648/96 3. i farmaci registrati all’estero, previsti dai protocolli clinici concordati dai Presidi di rete col Centro di Coordinamento
  52. 52. ACCESSO AI FARMACI Il competente medico specialista del Presidio di rete predispone il piano terapeutico (PT) attraverso la compilazione dell’apposita scheda per la prescrizione dei farmaci Copie di detta scheda dovranno essere fatte pervenire: 1. al medico curante dell’assistito (MMG o PLS) 2. alla ASL di residenza dell’assistito
  53. 53. ACCESSO AI FARMACI La fornitura dei farmaci deve avvenire tramite: 1. il Presidio di rete somministrazione ambulatoriale dei prodotti 2. la ASL di appartenenza del paziente farmaci necessari al trattamento dei pazienti inseriti nei programmi di assistenza domiciliare farmaci di fascia H farmaci non registrati in Italia e/o compresi nell’elenco AIFA legge 648/96 per le terapie domiciliari 3. Le farmacie aperte al pubblico farmaci di classe A e C, per le terapie da assumere al domicilio al di fuori di programmi di assistenza domiciliare

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