Oggi possiamo curare meglio le
1
Oggi possiamo curare meglio le malattie rare ?
Arrigo Schieppati
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
Rare diseases: the facts
�>50% are pediatric
�>85% are serious/life-threatening
�Chronic
�No effective treatment available
�Heterogeneous�Heterogeneous
�Very vulnerable, underserved populations
JM Walshe BMJ 1975 4
US Orphan Drug Act - 1983
�Tax incentives
�Exclusive or modified patent protection
�Priority Review
�Grants from FDA
�Amendments to antitrust laws to permit limited �Amendments to antitrust laws to permit limited exchange of data, pooling of resources, other collaborative efforts
�Government purchase of orphan drugs
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 � 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
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
A. Rappagliosi 8
Disease affecting no more than 5/10,000 persons in the EU
Profitability criteria:Need for incentives to justify the investment
Underlying Principles
�Equity
« Patients suffering from rare conditions should be entitled to the same quality of treatment as other patients. »
�Investment
9A. Rappagliosi
�Investment
« Promising drugs to treat these conditions would not be developed unless specific measures are taken to stimulate research and development of orphan drugs»
Underlying Principles
�Access
« The purpose of this regulation is…. to provide incentives for the research, development and placing on the market, of designated OMPs. »
A. Rappagliosi 10
« 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…»
ORPHAN DRUGS AVAILABLE: 12
• alemtuzumab • imiglucerase
Orphan Drug in Europe: Before 2000
• alemtuzumab
• alitretinoin
• deferiprone
• factor VII A
• factor IX
• factor IX
• imiglucerase
• mercaptimine
• phenylbutyrate
• protein C
• riluzole
• temozolomide
Joppi, Bertelè, Garattini B J Clin Pharm 2006 11
250
300
350
400
450
500
550
292
365
463
536
EMEA: Orphan drug designation and marketing
2001 2002 2003 2004 2005 2006 2007 20080
50
100
150
200
250
58
96
145
212
3 7 12 18 22 30 42 47
designation marketing
ORPHAN DRUG DESIGNATIONS 536
Orphan Drug in Europe: 2000-2008
ORPHAN DRUGS APPROVED 47
8 %13
FDA: Orphan drug designation and marketing
1500
2000 1951
Orphan drug designation and marketing (N)
83
0
500
1000
325
designation marketing
20081983
ORPHAN DRUG DESIGNATIONS 1951
Orphan Drug in USA : 1983 - 2008
ORPHAN DRUGS APPROVED 325
16.6 %15
ORPHAN DRUG DESIGNATIONS 23
Orphan Drug in Europe: 2000-2004
DRUGS APPROVED UNDEREXCEPTIONAL CIRCUMSTANCES 12
51%Joppi, Bertelè, Garattini B J Clin Pharm 2006 16
� 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
Under exceptional circumstances
comprehensive information cannot be provided
� it would be contrary to generally accepted principles of medical ethics to collect such information
17
Marketing authorisation may be granted on the following conditions:
�Complete the studies and reassess risk/benefit profile
Under exceptional circumstances
�Drug dispensation only through hospitals
�Patients and doctors well informed about the limited evidence of efficacy
18
Drug Disease Prevalence N. Pts
Algasidase Fabry 0.25 41Anagrelide Essential 2-3 1446
throbocytemiaArsenic trioxyde APML NA 52Bosentan Pulm Hypert0.005 32Carglumic ac, NAG synth def 0.000125 20Celecoxib Fam. Polyposis 0.3 970Celecoxib Fam. Polyposis 0.3 970Cladribine Hairy Cell L NA 120Ibuprofen Patent ductus NA 131Iloprost Pulm Hypert0.005 203Imatinib CML 0.18 1225Laronidase MPS1 0.025 45Migulstat Gaucher 0.33 28Mitotane Adrenal CA 0.1 500Pegvisomant Acromegaly 0.5 112Porfimer Na Barrett’s esop 2.3 208Zync acet. Wilson 0.6 148
19
• ALGASIDASE- αααα/ ALGASIDASE- ββββ FABRY DISEASE
• MIGLUSTAT / IMIGLUCERASE GAUCHER
• ARSENIC TRIOXIDE / RETINOIC ACID PROMYELOCITIC
LEUKEMIA
• BOSENTAN / ILOPROST / PULMONARY
• SILDENAFIL / HYPERTENSION
Orphan Drugs for the same indication: no comparative studies
• SILDENAFIL / HYPERTENSION
• IBUPROFEN / INDOMETHACIN PATENT DUCTUS
ARTERIOSUS
• CLADRIBINE / IFN-ALPHA HAIRY LEUKEMIA
• ZICOTINIDINE / MORPHINE INTRATHECAL
ANALGESIA
Joppi, Bertelè, Garattini B J Clin Pharm 200620
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�SMALL NUMBER OF PATIENTS
�POOR KNOWLEDGE OF ADVERSE REACTIONS
Joppi, Bertelè, Garattini B J Clin Pharm 2006 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
Itraconazole to Prevent Fungal Infections in Chronic Granulomatous Disease
John I. Gallin, M.D., et al. 2003
Thirty-nine patients with chronic granulomatous Thirty-nine patients with chronic granulomatous disease were enrolled in the study.
Accrual lasted from October 1991 to March2000.
�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 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 "prevention", or "delay of progression" in a six-month or one-year clinical trial for a chronic disease that has slowly evolving symptoms?
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
�Diseases classified as rare, available in thedatabase of the Information Center for RareDiseases (ICRD), IRFMN
�The first 50 diseases, sorted by the
QUALITY OF PUBLISHED RCT IN RARE DISEASES
Robinson KA., Int J Epidemiol, 2002
�The first 50 diseases, sorted by thenumber of contacts at May 23, 2003
�Identification of Randomized Clinical Trials(RCT) in MEDLINE was done, according to therecommended Cochrane search strategy forretrieval of reports of controlled trials
Rare diseases selected (50)
Rare diseases with potentially interesting abstract reviewed (49)
Rare diseases with at least one RCT identified (27)
Excluded (1) (No interesting title)
Excluded (22) (non randomized or reviews)
Excluded (7) (cross-over: 2) identified (27)
Rare diseases with at least one eligible RCT identified (20)
Rare diseases with at least one eligible RCT evaluated (18)
(cross-over: 2) (other reasons: 3) (cross-over + other reasons: 2)
Excluded (2) (not found)
Titles identified through the bibliographic search (7,410)
Potentially interestingabstracts reviewed (1,026)
Excluded (6,384) (No interesting title: 6,252) (No abstract available: 132)
Excluded (855) (Non randomized or reviews)
Abstracts with an RCT identified (171)
Potentially appropriate RCTs (107)
RCTs included (79)
Excluded (64) (Cross-over: 37) (Different disease: 12) (Other reasons: 15)
Excluded (28) (Full article not available)
80
60
40
%
51 %45 %
40
20
0No difference In favour of
STANDARD treatment
In favour of EXPERIMENT
ALtreatment
4 %
80
60
40
%74 %
40
20
0Surrogate endpoints
Survival
26 %
QUALITY OF PUBLISHED RCT IN RARE DISEASES
�Weak points found
- Power calculations
- Interim analyses/early stopping rules
- Recruitment period definition- 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
QUALITY OF PUBLISHED RCT IN RARE DISEASES
�Whenever feasible, RCTs in rare diseasesshould be performed with the highest standards.Weak points found in RCTs on common diseasesbecome issues of great concern in rare diseasesbecome issues of great concern in rare diseases
�When applicable, novel approaches should bebetter implemented, particularly when focused onsaving the number of patients enrolled
Halpern SD et al.. JAMA, 2002
Lagakos SW., N Engl J Med, 2003
European Clinical Research Infrastructures Network
www.ecrin.org
SwedenSweCRIN
GermanyKKS
DenmarkDCRIN
UKUKCRN
Ireland ICRIN
EFGCP
Austria
EORTC
FinlandFinnCRIN
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FranceInserm
Spain SCReN Italy
IRFMN & CIRM
HungaryHECRIN
National networks of Clinical Research Centres / Cl inical Trial Units
AustriaATCRIN
SwitzerlandSCRN
Challenges to clinical research in Europe
�Main bottlenecks :
Access to patients: fragmentation of health systems
Cost: fragmentation of public funding
Quality of infrastructures
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’
2001
1991
Gaucher’s disease
Imiglucerase
One year treatment with imiglucerase:
38
imiglucerase:
400.000$
FBignami: 6th ERTC workshop Barcelona ona - 9 July 200739
40FBignami: 6th ERTC workshop Barcelona ona - 9 July 2007
41FBignami: 6th ERTC workshop Barcelona ona - 9 July 2007
Time to availability of OMPs
Time to availability of OMPs
In Italy
OD with market autorization in EU 44
Available in Italy 27
Days before MA in Italy 437
Range 106-1004
44Source of Data: ISS web page. Data at March 31, 2008
OMP price in EU
�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
47FBignami: 6th ERTC workshop Barcelona ona - 9 July 2007
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.
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
Trends in Orphan Product Development
�Targeted therapies
�Recombinant therapies
�Monoclonal antibody therapies
�Gene therapy
Problems Encountered
Cost + Access
� Loss of some orphan drugs
� Drug prices
� Access remains an issue
And So…
�Orphan Products Development in the US and EU has proved beneficial for
Patients
Families
IndustryIndustry
Economy
PRESCRIZIONE OFF-LABEL
1. assunzione di responsabilità da parte del medico prescrittore
il paziente non può essere utilmente trattato con medicinali autorizzati
l’impiego del medicinale proposto è sostenuto da studi clinici almeno di fase II[Legge Finanziaria 2008]
prescrizioneoff-label per Malattia Rara=
prescrizione off-label per Malattia
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
Malattia NON Rara
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
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
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 domiciliareprogrammi 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