10/10/2008. Orphan drugs. Orphan drugs. Legislation Prevalence and evolution Slicing Cost. Raw materials Rare diseases: capita selecta Conclusions

Transcription

1 Orphan drugs Orphan drugs Definitions Definitions Legislation Prevalence and evolution Slicing Cost Dispensing Raw materials Rare diseases: capita selecta Conclusions 1

2 Definition: Orphan disease The term orphan disease implies two separate but related concepts. To describe diseases that are overlooked by doctors, and has been applied, for example, to Fabry's disease, alveolar echinococcosis, variant renal cancer, high myopia, and even some common conditions, such as endometrial cancer and tobacco addiction. However, more specifically the term orphan disease is used to designate diseases that affect only small numbers of individuals (socalled health orphans). Aronson, Br J Clin Pharmacol March; 61(3): Definition: Orphan disease Prevalence less than USA : 1/200,000 Japan : 1/50,000 Australia : 1/2,000 Europe : 5/10,000 WHO : /10,000 Aronson, Br J Clin Pharmacol March; 61(3):

3 Definition: Orphan disease A disease which has not been "adopted" by the pharmaceutical industry because it provides little financial incentive for the private sector to make and market new medications to treat or prevent it. accessed Lists of orphan diseases known rare disorders Different organisations NORD : National organisation of rare diseases NIH : National institutes of health Eurordis : European organisation of rare diseases Orphanet : Orphan drugs network Affecting 6-8 % of the population (EU : 25 million patients) Definition of orphan drugs EMEA/290072/2007 The term "orphan drug" refers to a product that treats a rare disease affecting fewer than 1 per 200,000 Americans accessed

4 Where do they come from? Intentionally developed (eg Tasigna) Unintentionally developed (eg Thalidomide) Target Market Designer drugs Shelf drugs RIP Recreational/malafide use (e.g. PCP) Orphan drugs Legislation: orphan drug status USA : Orphan drug act (ODA) Since January 1983 Incentives to encourage companies Tax reductions Extended marketing exclusivity (+ 7 years) Success? : 250 drugs authorised : 10 such drugs on market Haffner, N Engl J Med Feb 2;354(5):

5 Legislation: orphan drug status Europe :EMEA COMP Committee on orphan medicinal products Since 2000 (Verordening (EG) 141/2000 dd ) Incentives to encourage companies Protocol assistance Financial benefits (fee reduction) Marketing exclusivity (10 years) European registration (all countries) Procedure EMEA/COMP EMEA protocol assistance Start at day 1 Study by COMP Advice COMP at day 90 Advice tot EC Conclusion of EC Within 30 days Publication A new orphan drug is born Not yet authorised for marketing for desired indication (other procedure) 5

6 Orphan Evolution : ATC ATC/authorisation ATC/authoristaion ATC/Authoristion ATC/Autorisation date date date % 5% 7% 5% 2% 5% 27% 30% 33% 34% 33% 44% 38% 42% 3% 2% 40% 5% 42% 4% 2% 2% 4% 3% 8% 5% 7% 5% 5% 5% 3% 5% 3% 8% 8% 6% 6% 6% Enzyme Antithrombotic Cardiac Antihypertensive t i Urologic Hypothalamic Enzyme Antithrombotic Cardiac Antihypertensive Urologic Urological Hypothalamic Hypothalamic Antineoplastic Antineoplastic Analgesic Analgesic Other Antineoplastic Enzyme Enzyme Immunosuppressive Antithrombotic Antithrombotic Analgesic CardiacAntihypertensive Antihypertensive Antiepileptica Hypothalamic Hypothalamic Other Antineoplastic Antineoplastic It started with enzymetherapy Shift toward antineoplastic drugs 6

7 Authorisation per administration route 49% 51% Oraal Parenteraal No specialised administration necessary in all cases. Treatment in ambulatory care is possible. Prevalence Prevalence/

8 slicing to orphan diseases Possible to slice a disease into types If prevalence small enough orphan disease. Leukemia Started as 1 disease AML, CML, ALL, CLL : common known Now 18 subtypes defined Different types recognized as orphan disease and treated with orphan drugs (eg. chloretazine, oxaliplatin, ) USA Y. Waknine, 2004 Rocket science at high cost? Mostly academic research Subsidized by EC (EMEA) Small patient populations Multinational, multicentric research Lower level of evidence (p<0.05??) Case reports >> RCT Financial risk when not protected 8

9 Rocket science at high cost? High-tech synthetisation Enzymes : Aldurazyme, Myozyme, Older products, new name Thalidomide (Softenon) Existing molecule, different route Pedea (= ibuprofen) Rocket science at high cost? Simple molecule, same administration Wilzin (= zinc acetate capsules) Treatment of Wilson s disease Existing product, different name Hydroxycarbamide Hydrea versus Siklos Sildenafil Viagra versus Revatio 9

10 The right price? The right price? Very expensive therapies -pharmacokinetic challenge to calculate cost-utility (QALY s)? Can raise ethical questions -EMEA states that every citizen has the right to receive healthcare. (Maastricht treaty, December 1991) 10

11 The right price? Nitisinone : herbicide (low price) = NTBC ( 58 / 10 mg) = Orfadin (= 5,8 M /kg) 400 x Hydroxycarbamide =Hydrea ( / 500 mg) =Siklos ( 600 / month) The right price? Fromorphan to blockbuster Remicade Epogen The Orphan Drug Backlash (Scientific American May 2003:71-77) Definition of ultra-orphan drugs Prevalence less than 0.18 / 10,000 Orphan drugs and the NHS: should we value rarity (McCabe, BMJ 2005;331: ) 11

12 The right price? Wilzin Zinc acetate capsules Price 1.25 / 50 mg No UD packing Aspirin Acetyl salicylic acid Price 0.08 / 100 mg UD packing > 230 x price raw material The right price? Glivec 2660 / box Tasigna 4226 / box Myozyme 556 / vial Aldurazyme 651 / vial Sprycel 4528 / box Savene / vial Who will/can pay? 12

13 IPLEX(TM) is a complex recombinant human insulin-like growth factor-i (rhigf-i) and its predominant binding protein IGFBP-3 (rhigfbp-3). 13

14 Dispensing orphan drugs Expensive Reimbursed medication 7,11 allowance per box While handling cost = % of stock cost Risk management programs Thalidomide Revlimid (lenalidomide) 14

15 Raw materials Orphan Op drugs regulated ed by EMEA If producing them is not lucrative Not available as orphan drug Not available as pharmaceutical grade Can be available as chemical grade primary material Orphan raw materials A problem in tertiary care hospitals Legislation Royal Decree Pharmacist has to use licensed materials Magistral versus officinal preparations Certificate of analysis Update 2008 (to be published) Better quality assurance by distributor Magistral preparations only with licensed materials Request to adapt the RD Use of orphan raw materials in hospitals 15

16 Ethics versus politics Phosphomannose isomerase deficiency: A carbohydrate-deficient glycoprotein syndrome with hepatic-intestinal presentation Can be treated by supplying D-mannose to the patient Not available as brand drug nor as raw material pharmaceutical grade Available as chemical grade substance (purity > %) Not allowed by law Yet it makes the difference in quantity and quality of life Jaeken et al., A J Hum Genet 62 (1998), pp Orphan Diseases Task Force (UZL) Survey UZL Over 100 orphan diseases reported 18 orphan drugs and 11 orphan raw materials Total budget 7,000,000 (2007) Requested foundation of Leuven coordination center for rare diseases and their treatments Purpose : administrative support e.g. reimbursement by convention Soon available: 16

17 Autosomal recessive Pompe disease Glycogen storage disease type II Autosomal recessive metabolic disorderd Deficiency in the enzyme acid maltase Needed to break down glycogen Build-up of glycogen causes progressive muscle weakness (myopathy) and affects various body tissues (particularly in the heart, skeletal muscles, liver and nervous system) 17

18 Pompe disease First described by Johann Pompe in Infantile, or early onset Noticed shortly after birth Symptoms: severe lack of muscle tone, weakness, enlarged liver and heart. Mental function is not affected. Development normal for the first weeks or months but slowly declines. Most children die before age of 2 years by respiratory / cardiac complication. Juvenile and adult onset Symptoms: generalized muscle weakness and wasting of respiratory y g g y muscles in the trunk, lower limbs, and diaphragm, respiratory distress, headache at night. Intellect is not affected. A small number lives without major symptoms or limitations. 18

19 Pompe disease Therapy Alfa-glucosidase Recombinant human enzyme Replaces the missing enzyme Breaks down glycogen. Prolongs ventilator-free survival and overall survival Studied by Genzyme Now commercial available as Myozyme Started in a study as alfa-glucosidase Frozen solution at -80 C Cooled solution Lyophilized powder Commercial available 19

20 Pompe disease Preparation by pharmacist Preparation in LAF by hospital pharmacist Started as study medication 2 hours stable after defrosting patient had to come to hospital 8 hours stable after defrosting medication transported by taxi Less expensive as hospital admission Problem with aggregation during transport Company suggests no transport Use of particle inline filter to protect patient Use of human albumine to buffer problem solved 24 hours stable after preparation Therapy makes difference between live and dead Unpredictable prognosis Fabry disease Autosomal recessive metabolic disorder Deficiency in the enzyme alpha-galactosidase Accumulation of a glycolipid in vessels and tissue (globotriaosylceramide) Symptomatical treatment Symptoms: skin lesions, cornea verticilla, renal and cardiac complications Treatment by enzyme substitution Agalsidase alpha (Replagal) Agalsidase beta (Fabrazyme) Infusion every 2-3 weeks 20

21 Pulmonary arterial hypertension Symptoms Short breath, diziness, fainting, heart failure Arterial hypertension Vasoconstriction Right ventricle enlargment (pumping) Heart failure and long fibrosis Venous hypertension Left hearth failure pooling blood in lungs Treatment : diuretic, betablocker, ace-inhibitor, valvesurgery Pulmonary arterial hypertension 21

22 Pulmonary arterial hypertension Treatment Conventional: lifestyle changes, digoxin, diuretics, oral anticoagulants, and oxygen Prostaglandins: Epoprostenol (Flolan, synthetic prostacyclin) Continuous infusion in central venous catheter Instability (t ½ = 5 ) : on ice during administration Treprostinil (Remodulin) IV Oral and inhalation in developping Iloprost (Ilomedine) : longer t ½ IV Inhalation : Ventavis (US) Beraprost (oral Japan and Korea) Pulmonary arterial hypertension Treatment Endothelian receptor antagonist Bosentan (Tracleer) Sitaxentan (Thelin) Phosphodiesterase inhibitors Sildenafil (Viagra) Sildenafil (Revatio) Surgery Lung transplant Varia L-Arginine (Heartbar) 22

23 Very expensive therapy Surviving until surgery Partially financed by BSF (limited resources / budget) Parkinson Duodopa (Belgium) Need steady level of dopamine When regular treatment fails Severe parkinson, on-off fluctuations Swith oral intestinal administration Variability plasma level : % Levodopa and carbidopa in intestinal gel Administration by pump Stability 15 weeks in fridge; 16 h at 40 C 45,000 / year / patient 23

24 Wilson disease Autosomal recessive genetic disorder Copper accumulates in tissues Symptoms Liver disease (tiredness, hepatic encephalopathy, ) Neurological and psychiatric problems (cognitive deterioration, Parkinson-like, migraine, depression, psychosis, ) Keyser-Fleischer rings in eyes Calciumaccumulation in kidneys, cardiomyopathy, hypoparathyroidism, Wilson disease Treatment Low copper diet (mushrooms, nuts, chocolate, ) Copper chelation by penicillamin to reduce levels Zinc acetate to maintain low Cu-levels Activation of metallothionein, a protein in the gut, that binds copper so it cannot be adsorbed and transported to the liver. Liver transplant 24

25 Conclusions Orphan drugs Definition depends on continent Need depends on population Status versus needs (eg raw materials) Mostly very expensive therapies Mostly live saving for a small population Pharmacist has an important role Advising, preparing, dispensing, reimbursement EMEA is supporting Ethical discussions are possible Reflections Orphan drugs have a special status Prevalence, profit, availability, legislation, Similar? Compassionate use Medical need Conventions Clinical trial Off label use (especially in pediatrics, ) Drug orphans versus Orphan drugs 25

26 Orphan drugs in Europe Geneesmiddel Vorm Actieve stof Firma Telefoon Fax Terugbetaling? ALDURAZYME fl 500E Laronidase Genzyme nv 02/ / Ja ATRIANCE vial 250 mg/50ml Nelarabine Glaxo Nee BUSILVEX amp 6 mg Busulfan Pierre Fabre 02/ / Nee CARBAGLU tabl 200 mg Carglumic acid Orphan Europe 02/ / Ja CYSTADANE gr poeder Betaïne Orphan Europe Benelux 02/ / Nee DIACOMIT caps 500 mg Stiripentol Biocodex Nee EVOLTRA Fl 20 mg Clofarabine Quintiles Nee EXJADE tabl 125 & 250 & 500 Deferasirox Novartis Pharma 02/ /246.15/00 Ja mg FABRAZYME fl inj 35 mg Agalsidase beta Genzyme nv 02/ / Ja GLIOLAN sir 30 mg/ml 5-Aminolevulinezuur Medac Nee GLIVEC caps 100 & 400 mg Imatinib Novartis Pharma nv 02/ / Ja INOVELON tabl 100 mg Rufinamide Novartis Pharma nv 02/ / Nee LITAK amp 10 mg/5 ml Clabridine Lipomed Nee LYSODREN tabl 500 mg Mitotaan Laboratoire HRA Pharma Nee MYOZYME vial 50 mg Recombinant-human & glucosidase Genzyme NV 02/ / Ja NAGLAZYME amp 1 mg/ml Galsufase Biomarin 0477/ / Nee NEXAVAR tabl 200 mg Sorafenib tosylate Bayer 02/ / Ja ONSENAL caps 200 mg Celecoxib Pfizer 02/ / Nee ORFADIN caps 10 mg Nitisinone Orphan Europe 02/ / Ja PEDEA amp 10 mg/2 ml Ibuprofen Orphan Europe Benelux 02/ / Nee PHOTOBARR Fl 15 mg/ fl 75 mg Porfimer sodium Nee PRIALT Fl 100 mg/ml Ziconotide Eisai Pharma Nee REPLAGAL vial 3,5 mg/3,5 ml Agalsidase alfa TKT 5S AB Ja REVATIO tabl 20 mg Sildenafil Pfizer 02/ / Nee SAVENE Fl 500 mg Dexrazoxane Topotarget Nee SOMAVERT amp 10mg/15 mg/ Pegvisomant Pfizer 02/ / Ja 20mg SPRYCEL tabl 20 & 50 & 70 mg Dasatinib Bristol-Myers-Squibb 02/ / Ja SUTENT caps 12,5 & 50 mg Sunitinib Pfizer 02/ / Ja THELIN caps 100 mg Sitaxentan sodium Nee TRACLEER tabl 62,5 & 125 mg Bosentan Pharma Logistics 02/ / Ja TRISENOX amp 10 mg/10 ml Arsenic trioxide Cell Therapeutics Ja VENTAVIS Iloprost Nee WILZIN caps 25 & 50 mg Zinc acetate Orphan Europe Benelux 02/ / Nee XAGRID caps 0,5 mg Anagrelide Pharma Logistics 02/ / Ja XYREM 500 mg/ml Sodium oxybate UCB Pharma 02/ Nee ZAVESCA tabl 100 mg Miglustaat Pharma Logistics 02/ / Ja Orphan drugs outside Europe Geneesmiddel Vorm Actieve stof Firma Telefoon Fax Terugbetaling ADVATE fl inj 5 ml 500E Octocog alfa (recombinante stollingsfactor Baxter Hyland 02/ / Ja VIII) ADVATE fl inj 5 ml 1000E Octocog alfa (recombinante stollingsfactor Baxter Hyland 02/ / Ja VIII) BERINERT amp 500E C1-esteraseremmer ZLB Behring 016/ / Nee FERRIPROX tabl 500 mg Deferiprone OPG Medico Ja FLOLAN fl IV 500 mcg Epoprostenol Glaxo Smith Kline nv 02/ / Nee FLOLAN fl 1,5 mg + 2x50 ml solv Epoprostenol Glaxo Smith Kline nv 02/ / Nee HELIXATE NEXGEN fl 250E Octocog alfa (recombinante stollingsfactor ZLB Behring 016/ / Ja VIII) HELIXATE NEXGEN fl 500E Octocog alfa (recombinante stollingsfactor ZLB Behring 016/ / Ja VIII) HELIXATE NEXGEN fl 1000E Octocog alfa (recombinante stollingsfactor ZLB Behring 016/ / ja VIII) ILOMEDINE amp 0,05 mg Iloprost-tromethamine Schering nv 02/ / Nee KOGENATE fl 250IU Octocog alfa (recombinant coagulation Bayer Pharma 02/ / Ja factor VIII) KOGENATE fl 500IU Octocog alfa (recombinant coagulation Bayer Pharma 02/ / Ja factor VIII) KOGENATE fl 1000IU Octocog alfa (recombinant coagulation Bayer Pharma 02/ / Ja factor VIII) NOVOSEVEN 4,8 mg (240KUI) Eptacog alfa (geactiveerd) Novo Nordisk 02/ Ja NOVOSEVEN 60 KUI (1,2 mg) Eptacog alfa (geactiveerd) Novo Nordisk 02/ Ja NOVOSEVEN 240 KUI (4,8 mg) Eptacog alfa (geactiveerd) Novo Nordisk 02/ Ja PROLASTIN fl 40 ml 1000 mg Alpha 1-Proteinase Inhibitor (Human) Bayer Pharma 02/ / Nee PROLEUKIN fl IV 1 mg 18 milj Recombinant humaan Interleukin-2 Red Swan pharma logistics 02/ / Ja PULMOZYME inhal amp 2,5 mg/2,5 ml Dornasum alfa Roche nv 02/ / Ja REFACTO fl 500E Moroctocog alfa (recombinante Wyeth Pharmaceuticals nv 010/ / Ja coagulatiefactor VIII) REFACTO fl 1000E Moroctocog alfa (recombinante Wyeth Pharmaceuticals nv 010/ / Ja coagulatiefactor VIII) REFLUDAN fl IV 50 mg Lepirudine Pharma Logistics 02/ / Ja RILUTEK tabl 50 mg Riluzole Sanofi Synthelabo nv 015/ / Ja SOMATULINE autogel spuit inj 90 mg Lanreotide Ipsen nv 09/ / Ja SOMATULINE autogel spuit inj 60 mg Lanreotide Ipsen nv 09/ / Ja SOMATULINE autogel spuit inj 120 mg Lanreotide Ipsen nv 09/ / Ja SOMATULINE P.R. fl IM 20 mg/ml Lanreotide Ipsen nv 09/ / Ja THALIDOMIDE tabl 50 mg Thalidomide 0800/ / Ja THYROGEN kit 2xvial 1.1 mg + 2x10 Thyrotropine alfa Genzyme nv 02/ / Ja ml opl THYROGEN pulv. vr. inj. 0,9 mg Thyrotropine alfa Genzyme nv 02/ / Ja TOBI amp opl vr neb 300 mg/5 Tobramycinum Solvay Pharma & Cie 02/ / Ja ml XENAZYNE tabl 25 mg Tetrabenazine John Bell-Croyden Nee ZEFFIX tabl 100 mg Lamivudine Glaxo Smith Kline 02/ / Ja 26

27 Orphan-like drugs in Europe (before 2000) Geneesmiddel Vorm Actieve stof Firma Telefoon Fax Terugbetaling AMMONAPS gran940mg/g; Natriumfenylbutyraat Orphan Europe Benelux 02/ / Nee tabl500mg BENEFIX fl 500E Nonacog alfa (recombinant Baxter Hyland 02/ / Ja coagulation factor IX) BENEFIX fl 1000E Nonacog alfa (recombinant Baxter Hyland 02/ / Ja coagulation factor IX) BEROMUN fl IV 1 mg Tasonermine Boehringer Ingelheim 087/ / Ja nv CEREZYME 400E fl pulv. vr. inj. Imiglucerase Genzyme nv 02/ / Ja CYSTAGON caps 50 mg Mercaptamine Orphan Europe 02/ / Ja CYSTAGON caps 150 mg Mercaptamine Orphan Europe 02/ / Nee ORLAAM 10 mg / ml Levomethadyl HCl-acetaat Nee QUADRAMET Samarium lexidronam pentanatrium Nee VITRAVENE 6,6 mg/ml: 0,25 ml Fomivirsen natrium Nee Thank you for your attention Oliver Twist, story by Charles Dickens,