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British Journal of Clinical Pharmacology logoLink to British Journal of Clinical Pharmacology
. 2009 May;67(5):494–502. doi: 10.1111/j.1365-2125.2009.03369.x

Orphan drug development is not taking off

Roberta Joppi 1,2, Vittorio Bertele 1, Silvio Garattini 1
PMCID: PMC2686065  PMID: 19552743

Although, by definition, rare diseases involve few patients, there are so many – about 7000 (http://www.orpha.net/testor/cgi-bin/OTmain.php?&UserCell=publications) – that their epidemiological impact is impressive: 6–8% of the population is affected worldwide, with 30–40 million patients in the European Union (EU). This makes rare diseases a major public health issue [1]. However, the fragmented market means it is an area of little commercial interest for pharmaceutical companies, and the high price of orphan drugs tends to put them out of reach for the National Health Service [2].

Pinning-up measures

In the EU the European Medicines Agency (EMEA) recognizes the orphan drug status on the basis of epidemiological data (prevalence of the rare disease ≤5/10 000), medical plausibility, and potential benefit [3]. Orphan status designation implies incentives for pharmaceutical companies to develop orphan drugs, including 10 years of market exclusivity in the EU, protocol assistance to optimize development, guidance on preparing the dossier according to regulatory requirements, direct access to and fee reduction for the EMEA centralized procedures, including applications for marketing authorization, inspections, variations, and eligibility for grants from EU and Member State programmes and initiatives supporting research and development.

Has the long-term implementation of these facilities been really effective?

How many orphan drugs?

Since 2000, when the ad hoc legislation [3] came into force, up to 2007, out of 528 designated orphan indications related to 400 orphan medicinal products (OMPs) (http://ec.europa.eu/enterprise/pharmaceuticals/register/index.htm), only 45 (44 drugs) were approved (8.5%) after a mean of 34.8 months (range 6–76 months); out of the 70 OMP marketing authorization applications, 44 were approved (62.9%), 21 withdrawn (30%) and five rejected (7.1%). In the same period, out of 334 applications submitted for ‘non-orphan’ drugs, 236 (70.7%) were licensed (http://www.emea.europa.eu/htms/human/epar/a.htm).

Were orphan drugs developed properly?

Although preclinical data in the dossiers were fairly satisfactory (Table 1), repeated-dose toxicity studies were not always done in the two recommended animal species [4] for 10 OMPs or with long enough exposure [5] for 24. Lack of genotoxicity, carcinogenicity and reproduction toxicity studies was acceptable for recombinant products mimicking human enzymes (agalsidase alfa, agalsidase beta, aglucosidase alpha, galsulfase, idursulfase, laronidase) or anticancer agents (sorafenib, sunitinib, temsirolimus, trabectedin). In view of the nature of certain compounds, an incomplete toxicological dossier was also justifiable for drugs already on the market for more common indications (e.g. busulfan, ibuprofen and mitotane).

Table 1.

Pre-clinical data in orphan drugs’ dossiers

DRUG REPEATED DOSE TOXICOLOGY EXPOSURE GENOTOXICITY CARCINOGENICITY REPRODUCTION TOXICITY
Agalsidase alpha Rabbits; rats; monkeys 2–26 wks N.A. N.A. YES (not conclusive)
Agalsidase beta Rats 27 wks N.A. N.A. N.A.
Aglucosidase alfa Rat, mice, Cynomolgous monkey 4–26 wks N.A. N.A. YES (positive)
5-aminolevulinic acid hydrochloride Mice, rats, dogs 1–7 wks YES (negative in the dark and positive in the light) N.A. N.A.
Anagrelide Rats; Monkeys; Dogs; 12–52 wks YES (negative) N.R. YES (negative)
Arsenic trioxide Mice, rats, dogs, monkeys not specified YES (positive) N.R. N.R.
Betaine hydrochloride Rat 2–12 wks YES (negative) N.R. (natural component of mammalian cells) N.R.
Bosentan Rats; dogs; marmosets 1–4 wks YES (negative) YES (negative) YES (+ in rats, in rabbits)
Busulfan Dogs <1 wk N.A. N.R. YES (positive)
Carglumic acid Rats 2–18 wks YES (positive) YES (negative) YES (not conclusive)
Celecoxib Rats; dogs 24–52 wks YES (negative) YES (not conclusive) YES (positive)
Cladribine Mice 4 wks YES (positive) N.R. YES (positive)
Clofarabine Mice, rats, dogs not specified YES (positive) N.A. YES (positive)
Dasatinib Rat, Cynomolgus monkeys 4–36 wks YES (positive) N.A. YES (negative)
Deferasirox Rats, marmosets 2–39 wks YES (− in vitro; +/− in vivo) YES (negative) YES (negative)
Dexrazoxane Rats, rabbits, mice, dogs, swine 1–22 wks YES (positive) N.A. N.A.
Eculizumab Mice 4–26 wks N.A. N.A. YES (negative)
Galsulfase Cynomolgus monkeys 1–27 wks N.R. N.R. A full package of reproductive toxicity studies has not been conducted. Post-authorisation commitments have been agreed for further reproductive toxicity studies with toxicokinetics and clinical monitoring of pregnant animals
Hydroxycarbamide Rats; dogs; monkeys 1–12 wks N.R. N.A. YES (positive)
Ibuprofen N.R. N.R. YES (negative) YES (negative) YES (negative)
Idursulfase Cynomolgus monkeys 26 wks N.R. N.R. YES (negative)
Iloprost Rats; dogs 24–52 wks YES (negative) YES (negative) YES (positive)
Imatinib Monkeys 39 wks YES (+ in vitro and − in vivo) ongoing YES (positive)
Laronidase Dogs; monkeys 8–26 wks N.A. N.A. YES (not conclusive)
Lenalidomide Rats; monkeys 26–52 wks YES (negative) N.R. YES (positive) additional investigations requested
Mecasermin Rats; dogs 4–26 wks YES (negative) YES (positive) YES (negative)
Miglustat Rats; monkeys 4–52 wks YES (negative) YES (negative) YES (positive)
Mitotane N.A. N.A. N.A. N.A. N.A.
Nelarabine Mice, Cynomolgus monkeys 1–4 wks YES (positive) N.A. YES (positive)
Nilotinib Mice, rats, dogs, monkeys 26–39 wks YES (negative) N.A. YES (negative)
Nitisinone Mouse, rats, rabbist, dogs, Rhesus monkeys 12–48 wks YES (+ in vitro; − in vivo) N.A. YES (positive)
Pegvisomant Rats; Monkeys 24 wks YES (negative) N.A. YES (negative)
Porfimer Rats; Dogs 13 wks YES (positive) N.A. YES (negative)
Rufinamide Mouse, rats, Beagles, Cynomolgus monkeys, wild-caught baboons 4–52 wks YES (negative) YES (positive) YES (negative)
Sildenafil citrate Mice, rats, Beagles 12–48 wks YES (negative) YES (negative) YES (negative; but lack of data)
Sitaxentan sodium Mice, rats, dogs 1–39 wks YES (negative) YES (positive) YES (negative)
Sodium oxybate Rats, dogs 12–48 wks YES (negative) YES (negative) YES (negative)
Sorafenib tosylate Mice, rat, Beagles 12–48 wks YES (+ in vitro; +/− in vivo) N.A. YES (positive)
Stiripentol Mouse, rats Cynomolgus monkeys 4–26 wks YES (negative) YES (positive) YES (negative)
Sunitinib malate Rats, monkeys 4–12 wks YES (negative) N.A. YES (positive)
Temsirolimus Mice, rats, monkeys 12–36 wks YES (negative) N.A. YES (positive)
Trabectedin Mice, rats, dogs, Cynomolgus monkeys 1–3 wks YES (positive) N.A. N.A.
Ziconotide acetate Rats, monkeys, dogs 2–24 wks YES (negative) N.A. Not teratogenic; embryolethality observed
Zinc acetate Rats 53 wks YES (not conclusive) YES (not conclusive) YES (negative)

Legend to the table: N.A. = Not Available; N.R. = Not Requested.

Table 2 reports the main characteristics of the clinical studies in the dossier. Out of 44 approved OMPs, 24 (54.5%) received protocol assistance from the EMEA, 16 (36.4%) were authorized under exceptional circumstances, and two had a conditional marketing authorization, which means that the dossier was not complete and the EMEA required additional studies in order to maintain the authorization. Randomized controlled trials were done for 25 products (56.8%). In all the trials but three (5-aminolevulinic acid, deferasirox and porfimer) placebo was the comparator. It was used inappropriately in the case of anagrelide (hydroxyurea), arsenic trioxide (retinoic acid being an adequate control), bosentan, sidenafil and sitaxentan (epoprostenol), cladribine [interferon (IFN)-alpha], imatinib (IFN-alpha), ibuprofen (indomethacin), lenalidomide (bortezomib), miglustat (imiglucerase), pegvisomant (somatostatin), rufinamide (benzodiazepines or newer anti-epileptic drugs such as lamotrigine, topiramate or felbamate alone or as add-on to valproate), zinc acetate (tetrathiomolybdate, penicillamine or trientine), or ziconotide (morphin).

Table 2.

Orphan drugs’ clinical research and development

ACTIVE PRINCIPLE TRADE NAME INDICATION FREQUENCY OF INDICATION PROTOCOL ASSISTANCE DOSE FINDING TYPE OF TRIAL CONTROL END-POINT N. PATIENTS DURATION DESIGNATION DATE MA DATE NOTES Δ months§
Agalsidase alpha Replagal Fabry disease 1/40,000 YES YES RCT PLACEBO Reduction of pain; reduction of GB3 (globotriaosylceramide); reduction of cardiac mass; improvement of renal function 41 18 wks; 24 wks; 18 wks; 18 mo 8/8/2000 04/05/2001** 9
Agalsidase beta Fabrazyme Fabry disease 1/40,000 YES YES RCT PLACEBO Reduction of GL-3 (globotriaosylceramide) 56 20 wks 8/8/2000 04/05/2001** 9
Aglucosidase alfa Myozyme Pompe disease (acid α-glucosidase deficiency) 0.137/10,000 EU population NO NO 1 = Phase II/III uncontrolled study; 2 = Phase II uncontrolleed study NONE 1 = Percentage of patients alive and free of invasive ventilator support (endotracheal tube) at 12 months of age, when compared to a comparable historical untreated cohort derived from the Natural History study; 2 = survival 1 = 18; 2 = 21 1 = 52 wks; 2 = 52 + 52 wks 2/14/2001 3/29/2006 1 supportive study (extension) 61
5-aminolevulinic acid hydrochloride Gliolan Visualisation of malignant tissue during surgery for malignant glioma (WHO grade III and IV) 1/10,000 EU population YES YES Open label RCT WHITE LIGHT Percentage of patients without definite residual contrast-enhancing tumour seen on early (within 72 hours after surgery) postoperative MRI (Magnetic Resonance Imaging); progression-free survival six months after surgery 350 21 mo 11/13/2002 9/7/2007 58
Anagrelide Xagrid Essential thrombocythaemia 2–3/10,000 YES YES Open lable; non-randomized; uncontrolled NONE Platelet count less 600 × 109/L or reduction superior than 50% from baseline and maintenance of the reduction for at least 4 wks (= Complete Response) 1446 4–5 yrs 12/29/2000 16/11/2004** 47
Arsenic Trioxide Trisenox Acute promyelocytic leukemia 700–800/EU (yearly incidence) NO NO Uncontrolled phase II NONE Complete response; overall survival 52 15 mo 10/18/2000 05/03/2002** 17
Betaine hydrochloride Cystadane Homocystinuria 1.65/100,000 NO NO Case reports * NONE Plasma homocysteine 140 N.A. 7/9/2001</ 2/15/2007 67
Bosentan Tracleer Pulmonary arterial hypertension 1–2/106 year YES NO RCT PLACEBO Walk excercise 32 15 wks 2/14/2001 15/05/2002** 15
Busulfan Busilvex Conditioning haematopoietic progenitor cell transplantation 6.6/100,000 YES NO Uncontrolled phase II NONE Same effect of i.v. and oral busulfan 104 2,5 yrs 12/29/2000 7/9/2003 31
Carglumic acid Carbaglu N-acetyl glutamate synthase deficiency 0.00125/10,000 NO NO Retrospective study NONE Lower of ammonia level 20* 3,1 yrs 10/18/2000 24/01/2003** 27
Celecoxib Onsenal Familial adenomatons polyposis 03–1/104 NO NO RCT PLACEBO Decrease of colorectal polyps 970 6 mo 11/20/2001 10/17/2003 23
Cladribine Litak Nairy Cell Leukemia 4–5/106 year NO NO Uncontrolled phase II (+ literature analysis) NONE Complete + partial responses 120 9/19/2001 4/14/2004 31
Clofarabine Evoltra Acute lymphoblastic leukaemia (ALL) in paediatric patients 1/29,000 NO YES Phase II, non-randomized, open-label, single-arm NONE Complete remission (CR); complete remission without platelet recovery (CRp), partial remission (PR) 61 N.A. (every 2-6 wks, max. 12 cycles) 2/5/2002 5/29/2006 51
Dasatinib Sprycel Chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL) 0.9/10,000 (CML) and 0.71/10,000 (ALL) EU population YES YES Phase II open-label NONE 1-5 = haematological and cytogenetic response rate 1 = 424 2 = 166 3 = 197 4 = 124 5 = 101 N.A.; mean follow-up = 6 mo 12/23/2005 11/20/2006 11
Deferasirox Exjade Transfusional haemosiderosis in patients aged >2 years 102,000 persons in the EU YES YES 1 = phase III RCT, active-contolled, open-label; 2 = phase II open-label trial 1 = Deferoxamine; 2 = NONE Liver iron content 1 = 586 2 = 184 1/2 = 1 yrs 3/13/2002 8/28/2006 53
Dexrazoxane Savene Treatment of anthracycline extravasation 0.03/10,000 NO NO Open-label, single-arm studies, using an external control from the literature NONE 1/2 = proportion of patients undergoing surgery 1 = 23 2 = 57 1 = 2 yrs; 2 = 3 yrs 9/19/2001 7/28/2006 58
Eculizumab Soliris Paroxysmal nocturnal haemoglobinuria (PNH) in patients with history of transfusions 0,01/100.000 EU population YES NO 1 = Phase III RCT; 2= Phase III open-label study 1° = PLACEBO 1= Co-primary endpoints: haemoglobin stabilization and number of packed red blood cell (PRBC) units transfused; 2= haemolysis as mesured by LDH (lactate dehydrogenase) area under the concentration curve (AUC) 1= 75; 2= 97 1= 26 wks 2= 52 wks 10/17/2003 6/20/2007 44
Galsulfase Naglazyme Maroteaux-Lamy Syndrome (Mucopolysaccharidosis VI) 0.024/10,000 EU population NO YES 1 = Phase III RCT; 2 = Phase II open-label study 1 = PLACEBO; 2 = NONE 1 = 12-minute walk test; 2 = 12-minute walk test; stair climb test; urinary GAG (glycosaminoglycans) levels; Shoulder ROM (Range of Movement) 1 = 39 2 = 10 1/2 = 24 wks 2/14/2001 1/24/2006 59
Hydroxycarbamide Siklos Prevention of recurrent painful vaso-occlusive crises including acute chest syndrome in paediatric and adult patients suffering from symptomatic sickle cell syndrome <0.5/10,000 YES NO 1= Paediatric population: literature analysis 2 = Adults: RCT 1 =NONE 2 = PLACEBO 1 = Hospitalisation because pain episodes; number and lenght oh hospital admission; pain episodes 2 = mortality 1 = 378 2 = 299 1 = 6 mo − 7 yrs 2 = not clearly reported 7/9/2003 6/29/2007 47
Ibuprofen Pedea Patent ductus arteriosus (PDA) in preterm newborn infants (<34 weeks of gestational age) 42% in infants <1 kg at birth YES YES RCT; controlled (+ metanalysis) PLACEBO Proportion of patients requiring surgical ligation of PDA after prophylactic vs. after curative administration of i.v. ibuprofen 131 36 wks 2/14/2001 7/29/2004 41
Idursulfase Elaprase Hunter syndrome (Mucopolysaccharidosis II, MPS II). 0.02/100,000 EU population YES YES 1 = Phase II/III RCT 2 = Phase I/II open-label extension study 1 = PLACEBO 1 = Sum of the ranks of the change from Baseline to week 53 in the total distance walked in the 6-minute walking test (6MWT) and in % predicted forced vital capacity (FVC) 1 = 96 2 = 12 1 = 12 mo 2 = 6 mo 12/11/2001 08/01/2007** 61
Iloprost Ventavis Primary Pulmonary Hypertension 1-2/106 year YES NO RCT PLACEBO Improvement walk; Improvement of 1 NYHA (New York Heart Association) class 203 12 wks; 12 wks 12/29/2000 16/9/2003** 21
Imatinib Glivec Chronic Myeloid Leukemia (CML) Unresectable and Metastatic Malignant Gastrointestinal Stromal Tumours (GIST) CML=1.09/100,000 EU population GIST= 1.1-1.5/100,000/year YES YES Uncontrolled phase II NONE (CML) Hematological and cytogenetic response; (GIST) Tumor response 1= 1225; 2=147 254 days; 24 wks 2/14/2001 27/08/2001** 6
Laronidase Aldurazyme Mucopolysaccharidosis MPS-1 0.025/10,000 YES NO RCT PLACEBO Reduction of urinary GAG; reduction of hepatosplenomegaly; increase forced vital capacity (FVC); six-minute walk exercise tolerance test (6MWT) 45 3 yrs; 104 wks 26 wks 26 wks 2/14/2001 10/06/2003** 28
Lenalidomide Revlimid Multiple myeloma 21,500 new cases/year YES YES 1/2 = RCT 1/2 = PLACEBO 1/2 = time-to-progression (TTP) 1 = 353 2 = 351 1/2 = 12 mo 12/12/2003 6/14/2007 42
Mecasermin Increlex Severe primary insulin-like growth factor 1 deficiency (Primary IGFD) <2/10,000 EU population NO YES 1 = Phase III RCT 2 = Phase III open-lable 3 = open-lable study 1 = PLACEBO 1/2/3 = linear growth rate 1 = 8 2 = 23 3 = 8 1 = 15 mo 2 = 24 mo 3 = 24 mo 8/26/2005 03/08/2007** 24
Miglustat Zavesca Gaucher disease Type 1 1/30,000 YES NO Uncontrolled phase II NONE Reduction of liver and spleen volume 28 2 yrs 10/18/2000 20/11/2002** 25
Mitotane Lysodren Adrenal cortical carcinoma 0.1/10,000 YES NO Literature analysis NONE Survival; remission time; tumour size reduction 500 various time period 6/12/2002 4/28/2004 22
Nelarabine Atriance T-cell acute lymphoblastic leukaemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) 1.1/10,000 EU population YES YES Two Phase II open-label, non-comparative studies NONE 1 = Complete and partial responses (paediatric); 2 = Complete and partial responses (adults) 1 = 70 paediatric pts. (≤21 ys); 2 = 39 adults (≥16 ys) 1 = 1 yr; 2 = 1 yr 6/16/2005 22/08/2007** 26
Nilotinib Tasigna Chronic phase and accelerated phase Philadelphia chromosome positive chronic myelogenous leukaemia (CML) with resistance or intolerance to prior therapy including imatinib. 2.4/100,000 EU population YES YES Uncontrolled, unblinded, non-randomised Phase IA/II study NONE Major (complete + partial) cytogenetic response (MCyR) 132 12 mo 5/22/2006 11/19/2007 18
Nitisinone Orfadin Hereditary tyrosinemia type 1 (HT-1) 0.1/10,000 EU population NO NO Open-label, single-arm studies (based on compassionate use) NONE Survival, survival without transplantation, death due to liver failure, transplantation for liver failure and hepatocellular carcinoma 207 6,5 yrs 12/29/2000 21/02/2005** 50
Pegvisomant Somavert Resistant acromegaly 5–7/100,000 YES NO RCT PLACEBO Decrease in IGF-1 (Insulin-like Growth Factor-1) 112 12 wks 2/14/2001 11/13/2002 21
Porfimer sodium Photobarr Dysplasia in Barrett's oesophagus >0,5% Barret's Oesophagus population annualy YES NO RCT OMEPRAZOLE Complete responses 208 6 mo 3/6/2002 3/25/2004 2
Rufinamide Inovelon Lennox Gastaut syndrome in patients >4 years 1-2/100,000 (EU population) N.A. YES RCT PLACEBO Combined endpoint: A. reduction in total seizure frequency per 28 days in double-blind phase relative to the baseline phase was significantly greater (p < 0,025; two-sided) for rufinamide than placebo; B. both of the following end points were met: – reduction in tonic-atonic seizure frequency per 28 days in the double-blind phase relative to the baseline phase was significantly greater 8p < 0,025, two-tailed) for rufinamide than placebo; – the seizure severity rating from the Global Evaluation of the patient's condition was significantly greater (p < 0,025, two-tailed) for rufinamide than placebo 139 84 days 10/9/2004 1/16/2007 10 supportive study (3 extensions) 27
Sildenafil citrate Revatio Pulmonary arterial hypertension class III 1/10,000 NO NO RCT PLACEBO Six-minute walk exercise tolerance test (6MWT) 278 12 wks 12/12/2003 28/10/2005** 1 supportive study (extension) 22
Sitaxentan sodium Thelin Pulmonary arterial hypertension class III 2/100,000 NO YES RCT 1 = PLACEBO; 2 = PLACEBO (for descriptive comparison, an open-label bosentan arm was included); 3 = PLACEBO 1 = Change in percentage of predicted peak VO2 (oxygen uptake) from baseline to week 12 measured during cycle ergometry; 2/3 = change from baseline in six-minute walk exercise tolerance test (6MWT) at week 18 1 = 178 2 = 240 3 = 98 1/2 = 12 wks 3 = 18 wks 10/21/2004 8/10/2006 22
Sodium oxybate Xyrem Narcolepsy with cataplexy in adult patients. 5/10,000 NO NO RCT 1/2 = PLACEBO 1/ 2 = Total number of cataplexy attacks 1 = 136 2 = 55 1 = 2 and 4 wks; 2 = 2 wks 3/10/2005 7/19/2006 4 open-label supportive studies 16
Sorafenib tosylate Nexavar Hepatocellular carcinoma 3/10,000 EU population YES YES RCT PLACEBO Overall survival 769 1 = 29 mo 7/29/2004 7/19/2006 supportive study (discontinuation phase II RCT) 24
Stiripemtol Diacomit Severe and uncontrolled myoclonic epilepsy in infancy (SMEI, Dravet's syndrome) 0.4/10,000 NO NO RCT 1°/2° = PLACEBO 1°/2° = Number of responders: subjects with > 50% reduction in the number of seizures during the treatment peiod (2 months) 1° = 41; 2° = 24 3 months 12/5/2001 04/12/2007*** 4 supporting studies 72
Sunitinib malate Sutent Unresectable and/or metastatic malignant gastrointestinal stromal tumour (GIST) Metastatic Renal Cell Carcinoma (MRCC) 64,400 in EU N.A. YES GIST: RCT; MRCC: single-arm, open-labe GIST: PLACEBO MRCC: NONE GIST: Time to tumour progression (TTP) MRCC: complete and partial response (ORR) GIST: 312 MRCC: 106 GIST: 2 yrs MRCC: 11 mo 2/3/2003 13/10/2005*** 2 open-lable supportive studies 32
Temsirolimus Torisel First-line treatment of patients with advanced renal cell carcinoma 35/100,000 EU population YES YES Phase II, randomised, blinded, dose-comparing, parallel-group NONE Complete and partial responses 111 8 wks 4/6/2006 11/19/2007 19
Trabectedin Yondelis Soft tissue sarcoma 2/10,000 EU population NO YES Randomised open-lable study DIFFERENT SCHEDULE Time to progression (TTP) 260 24 mo 5/30/2001 17/09/2007** 76
Ziconotide acetate Prialt Severe, chronic pain in patients requiring intrathecal (IT) analgesia N.A. NO YES RCT PLACEBO 1–3 = Percentage change in Visual Analogue Scale of Pain Intensity (VASPI) 1 = 112 2 = 257 3 = 220 1/2 = 5–6 days; 3 = 3 wks 7/9/2001 21/02/2005** 2 supportive studies (the first two studies were prolonged into a long-term open-label study) 43
Zinc acetate dihydrate Wilzin Wilson's disease 0.6/10,000 NO YES Open label; non-randomized; uncontrolled NONE Effects on copper metabolism [24 h copper excretion and non-coeruloplasmin plasma copper (NCPC); effect on speech and neurological function measured on integer scale; effect on liver function tests (liver enzymes, bilirubin, albumin)] 148 3.2 yrs in symptomatic adults; 3.1 yrs in pre-symptomatic adults 7/31/2001 10/13/2004 39
*

reports retrieved from literature

**

MA under exceptional circumstances

***

conditional MA, Δmonths§ = difference between Designation date and MA date.

In 10 cases the approval was granted with an uncontrolled Phase II study; aglucosidase alpha, anagrelide, dexrazoxane, nitisinone and zinc acetate were authorized on the basis of open-label uncontrolled studies, and carglumic acid on the basis of a retrospective study; for mitotane and betaine only a literature analysis was submitted; this was also the case for hydroxylcarbamide in the paediatric population.

In 16 cases the number of study patients was <100, 10 drugs were tested in studies involving 100–200 patients, 13 in studies with 200–500 subjects, three in studies with 500–1000 and the remaining two drugs were studied in >1000 patients. Whereas for some very rare diseases the small number is justifiable, in other cases it is not: nelarabine was studied in about 100 patients out of 50 000 potential European cases of T-cell acute lymphoblastic leukaemia or T-cell lymphoblastic lymphoma; for Fabry disease the pivotal studies included 41 and 56 patients out of 10 000 potential cases in Europe. Similar figures apply to miglustat, tested on only 28 patients; and clofarabine, tested in 61 patients.

Has the clinical relevance of orphan drug benefit been proved (or even sought)?

Typically the primary end-points are surrogate. Biochemical parameters such as GL-3 (globotriaosylceramide), GB-3 (globotriaosylceramide), IGF-1 (insulin-like growth factor-1), GAG (glycosaminoglycans), homocysteine or ammonia are certainly relevant for the respective diseases, but there is very little proof that the extent of their change is clinically important, justifying long-term treatments. The same holds true for the short-term platelet count reduction by anagrelide. Similarly, the improvement in walking induced by drugs active in pulmonary arterial hypertension, and in mucopolysaccharidosis, although statistically significant, is of questionable clinical importance. The efficacy of anticancer drugs was measured through tumour responses or time to progression rather than survival or quality of life.

In some cases the trial was too short in relation to the natural history of the disease: 20 weeks for agalsidase-beta or 18 months for agalsidase-alpha in the treatment of Fabry disease; 12 weeks for pegvisomant acting on resistant acromegaly, for drugs active in pulmonary hypertension or in epilepsy; 4 weeks for anagrelide in essential thrombocythaemia or for sodium oxybate in narcolepsy all seem inadequate.

The dossiers of the 20 orphan drugs developed without protocol assistance always contain some deficiencies, but these are also present in 20 out of 24 seeking advice (Table 2).

Small numbers and poor evidence for a sizable public health burden

The epidemiological magnitude of rare diseases (7000) is possibly reflected by the number of orphan drug designations (528) but not by their approvals (44), and even less so by their availability on the market (only 26 in the Italian market, driven by a fairly generous national health service). Moreover, clinical and public health needs are poorly met by inadequately documented orphan drugs' efficacy and safety profiles. Limitations include frequent lack of dose-finding studies, often inappropriate clinical design or lack of active comparator where available, insufficient exposure to the treatment, surrogate end-points or weak proof of clinical benefit. The lack of reliable methods for evaluating the effect of drugs on small numbers of patients is also a factor in the general poor quality of the dossiers [6]. However, although less stringent criteria can be considered for orphan drugs than for drugs treating more common diseases, this cannot be an excuse not to guarantee the best possible treatments to patients with rare diseases. For a frequency from 5/10 000 to 5/100 000, at least 25 000–250 000 patients are to be found in the whole of Europe. This should allow adequately sized multicentre trials to test superiority over effective treatments, where available, in terms of clinically meaningful end-points. Longer marketing exclusivity should be granted in order to compensate the long-term follow-up of clinical outcome measures. Because of deficiencies in the documentation, the EMEA required follow-up studies for 18 drugs, which will not necessarily be done and in any case would take many years before the results are available.

It is a cause for concern that in spite of an ad hoc law, after 8 years orphan drugs in the EU are still few and poorly studied. Long-term data confirm previous evaluations in the early stages when measures aimed at promoting orphan drugs had still to be fully implemented [79], and cast doubt on the effectiveness of the current system.

It is not clear what discourages the pharmaceutical industry from developing so few orphan drugs out of the many designated, in spite of the market exclusivity, methodological facilities, and the willingness of the European health systems to pay the high costs and endure the possible low cost-effectiveness of these products.

Stakeholders need to reflect on these findings to foster new measures to providw an answer to this largely neglected clinical and social issue.

Competing interests

None to declare.

This work was funded by institutional funds from the Mario Negri Institute. The authors are grateful to Giuseppina Petruzzelli (G.A. Pfeiffer Memorial Library) and Judith Baggott for editorial assistance.

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