Oggi possiamo curare meglio le malattie rare ?

1. Oggi possiamo curare meglio le
malattie rare ?
Arrigo Schieppati
1

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. Rare diseases: the facts
>50% are pediatric
>85% are serious/life-threatening
Chronic
No effective treatment available
Heterogeneous
Very vulnerable, underserved populations

4. JM Walshe BMJ 1975 4

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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

12. 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

13. Orphan Drug in Europe: 2000-2008
ORPHAN DRUG DESIGNATIONS 536
ORPHAN DRUGS APPROVED 47
8%
13

14. FDA: Orphan drug designation and marketing
Orphan drug designation and marketing (N)
1951
2000
1500
1000
500 325
0
1983 2008
83
designation marketing

15. Orphan Drug in USA : 1983 - 2008
ORPHAN DRUG DESIGNATIONS 1951
ORPHAN DRUGS APPROVED 325
16.6 %
15

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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

22. 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

23. 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.

24. 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?

25. 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

26. 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

27. 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)

28. 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)

29. 80
%
60
51 %
45 %
40
20
4%
0
No difference In favour of In favour of
EXPERIMENT STANDARD
AL treatment
treatment

30. 80 74 %
%
60
40
26 %
20
0
Surrogate Survival
endpoints

31. 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

32. 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

33. European Clinical Research Infrastructures
Network
www.ecrin.org

34. 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

35. Challenges to clinical research in Europe
Main bottlenecks :
Access to patients: fragmentation of health
systems
Cost: fragmentation of public funding
Quality of infrastructures

36. 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’

37. Gaucher’s disease 2001
1991
Imiglucerase

38. One year treatment with
imiglucerase:
400.000$
38

39. 39
FBignami: 6th ERTC workshop Barcelona ona - 9 July 2007

40. 40
FBignami: 6th ERTC workshop Barcelona ona - 9 July 2007

41. 41
FBignami: 6th ERTC workshop Barcelona ona - 9 July 2007

42. Time to availability of OMPs

43. Time to availability of OMPs

44. 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

46. OMP price in EU

47. 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

48. 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

49. Trends in Orphan Product
Development
Targeted therapies
Recombinant therapies
Monoclonal antibody therapies
Gene therapy

50. Problems Encountered
Cost + Access
Loss of some orphan drugs
Drug prices
Access remains an issue

51. And So…
Orphan Products Development in the US and EU
has proved beneficial for
Patients
Families
Industry
Economy

53. 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

54. 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

55. 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

56. 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