Transcript No Slide Title

Rare Diseases and Orphan Medicinal Products
Máster en diagnóstico y terapia de las enfermedades raras
Josep Torrent-Farnell
Universitat Autònoma de Barcelona
Hospital de la Santa Creu i Sant Pau
Comité de Medicamentos Huérfanos, EMEA, Londres
22 marzo 2010
Universidad Internacional de Andalucía
1
Why a regulation for Orphan Medicines is needed?
• Some conditions occur so infrequently that the cost
of developing a medicinal product would not be
recovered by the expected revenues. Therefore the
pharmaceutical industry is unwilling to develop
these medicines under normal market conditions.
Patients suffering from rare conditions should be entitled to the
same quality of treatment as other patients
(EC Regulation No 141/2000)
2
Some facts on rare diseases (I)
• More than 6,000 rare conditions have been
identified (WHO)
• People affected by Orphan diseases(*)
• USA:
20 million
• EU:
25-30 million
• Spain:
3,5 million
(*)Estimate
figures
3
Some facts on rare diseases (II)
• More than 4,000 rare conditions are genetic in
origin and affect paediatric population
• People affected by inborn rare diseases
• 1/3 will die during the first year of life
• 1/3 will be handicapped for the span of life
• 1/3 will receive the most suitable treatment and
have an acceptable quality of life
4
Some facts on rare diseases (III)
• A major public health burden recognized as a health priority by the EU
(DG SANCO and DG Research)
• Causing severe deficits*:
» Motor (44 % of all RD)
» Chronic pain (22 %)
» Intellectual (6.5 %)
• Long-term permanent disabilities*:
» Undermining QoL/autonomy
» Partial limitations (37 %)
» Restricted autonomy (30 %)
» Reduced activity (23 %)
» Lack of autonomy (6 %)
* Data from Orphaned database
5
Some facts on rare diseases (IV)
•
An heterogeneous group of different clinical conditions affecting
potentially all organs and systems of the body and all ages.
•
They are life-threatening, serious and/or chronically debilitating,
impairing QoL and causing long-lasting disabilities and
dependences.
•
They are “invisible” by the society and often “unknown” by
health professionals.
•
Requires a multidisciplinary approach for its overall
management (genetic screening, pharmacologicals,
surgery,nutraceuticals, rehabilitation, specific educational
strategies, and social support).
6
Orphan conditions (RD) vs neglected diseases
• Neglected diseases are medical conditions (severe, lifethreatening and chronically debilitating) that have a high
prevalence in developing regions (“poor countries”) but they
display a low prevalence in developed regions (“rich
countries”)
• Some examples are: Tuberculosis, Malaria, HIV/SIDA, Chagas
disease, Leihmaniasis Buruli ulcer, sleep sickness, etc.
7
Some examples of Rare Diseases*
•
Hodgking and non-Hodgking Lymphomas
•
ELA
•
All types of Leukemias
•
Pompe Disease
•
More than 400 solid cancers conditions
•
Nieman-Pick-Disease
•
Multiple Mieloma
•
Gaucher Disease
•
Sarcoidosis
•
Fabry Disease
•
Graft-versus-Host Diseases
•
Polyarteritis Nodosa
•
Duchene Muscular Distrophy
•
Mucopolysaccharidosis
•
Friedreich Ataxia
•
Thalasemias
•
Leber Hereditary Optic Neurophaty (LHON)
•
Ewing Sarcoma
•
Laron Syndrome
•
Churg-Strauss Syndrome
* NORD, EURORDIS, ORPHANET, databases
8
Some examples of “Ultra Rare Diseases” > 1000 cases*
•
Cohen Syndrome
•
Larsen Syndrome
•
Seckel Syndrome
•
Gunther Disease
•
Kimura Disease
•
Ondine Syndrome
•
Möbius Syndrome
•
Coffin-Siris Syndrome
•
CHILD Syndrome
•
Li-Fraumeni Syndrome
* NORD, EURORDIS, ORPHANET, databases
9
Unmet medical needs for patients affected by rare
disorders require global and international joint efforts
10
Orphan Medicinal Products: International Overview
• United States ‘Orphan Drug Act’
1983
• Japan ‘Orphan Drug Legislation’
1993
• Singapore ‘Orphan Legislation’
1997
• Australia ‘Orphan Legislation’
1998
• Europe ‘Orphan Regulation’
2000
11
Orphan Medicinal Products in the EU
International Comparison
Europe
Orphan
Regulation 2000
-< 185000 Patients,
less than 5/10000
Inhabitants
USA
Orphan Drug Act -< 200000 Patients,
1983
less than 7,5/10000
Japan
Orphan Drug
Legislation 1993
-< 50000 Patients,
less than 4/10000
Inhabitants
Australia
Orphan Drug
Program 1998
- < 2000 Patients,
less than 1,1/10000
Inhabitants
12
Comparative Requirements for ODD
US
EU
6.8 / 10,000
5 / 10,000
Nature of disease
Rare
Life-threatening,
debilitating
Scientific rationale
YES
YES
Economic (lack of ROI)
YES
YES
Significant benefit (added therapeutic value)
NO
YES
“Medically plausible” subset
YES
YES
Before MA
Before MA
Humanitarian use
NO
Epidemiological “prevalence”
Time of application
Medical devices
13
Comparative Requirements for ODD
US
EU
7
10
MA fee–waiver
YES
YES
Protocol assistance/
scientific advice
YES
YES
Direct grants from
regulatory agency
YES (Clinical studies)
NO
Other public grants
YES (NIH)
YES (DG Research,
National)
YES (50% of clinical cost)
Depends on MS
Market exclusivity (yrs)
Tax credits
14
Orphan Medicinal Products: Legal Basis
• Legal Basis Medicinal Products
– Council Regulation (EEC) 2309/93
– Council Directive 2001/83/EG
– European Pharmacopoeia
• Legal Basis Orphan Products
– EUROPEAN PARLIAMENT and COUNCIL REGULATION
(EC) No 141/2000
– COMMISSION REGULATION (Ec) No 847/2000
15
Orphan Medicinal Products: Designation vs. Authorization (I)
• Authorization
– ensuring that only medicinal products that
are effective, safe and of good quality are
marketed.
• Designation
– providing incentives for the development
of medicinal products for the benefit of
patients suffering from rare conditions
16
Orphan Medicinal Products: Designation vs. Authorization (II)
Level of proof:
• Authorization
– scientifically proven fact (beyond reasonable
doubts)
• Designation
– reasonable scientific assumptions (hypothesis
based on solid scientific facts)
17
Some basic considerations (I):
Designation
•
Given by COMP is the “ENTRY GATE” and gives access to
several incentives and to centralised system
•
Epidemiological criteria (“one in two thousand”)
•
Does not lower the requirements when submitting and
application for M.A.
•
Are mainly intended to mobilise partnering and funding for
investigation in rare diseases
•
Several different (or “sameness”) active substances can be
designated for one specific orphan condition
18
Some basic considerations (II):
Marketing authorizations
• Are given by the CHMP assessment on the quality, safety
and efficacy data submitted for centralised applications
• Orphan-market-exclusivity rights are linked to the
approved therapeutic indication by the CPMP
• Prevents “me-too” drugs entering to the EU market
19
Orphan Medicinal Products
• Orphan Condition
– Any deviation from the normal structure and function of
the body, as manifested by a characteristic set of
symptoms, typically a disease or syndrome.
– Benefit from incentives
• Therapeutic Indication
– It will be the result of the assessment of the quality,
safety and efficacy data submitted with the marketing
application
– It may be more restrictive than the orphan condition
– Benefit from market exclusivity rights
20
COMP Composition
• The regulation establishes the Committee for Orphan
Medicinal Products (COMP), within the EMEA, which is
responsible for examining all applications for orphan
medicinal product designation submitted to it in
accordance with the Regulation.
• 33 Members:
– One member nominated by each of the Member States (27)
– Three members nominated by the Commission to represent
patients’ organisations (3)
– Three members nominated by the Commission on the basis of a
recommendation from the Agency (3)
21
Task of the Committee
• Scientific evaluation:
–
–
–
–
Orphan drug designation
Protocol assistance (through SAWP)
Significant benefit at the time of granting MA
5 years review (economic evaluation upon request
from MS)
• Public health activities:
– Advice Commission to establishment develop OMP
policy
– Liaising internationally and liaising with patient
groups
– Assist Commission in preparing guidelines
– EU Experts Network/ Increase visibility
Designation means investigational orphan products
22
EMEA
COMP
Advice on designation
Review
Applications
CHMP
Protocol Assistance
EU Panel
Experts
Scientific
Advice
Review
Applications
rare
diseases
Designation
‘Entry Level’
Marketing Authorisation
‘Outcome’
23
Orphan Designation Criteria
• Identifies ‘orphan’ products eligible for incentives
• Application from sponsor should demonstrate:
 life-threatening or debilitating nature of condition
 medical plausibility
 prevalence < 5 in 10,000 or unlikely to generate sufficient
return on investment no satisfactory methods exist or
medicinal product will be of significant benefit
• COMP Opinions
EC Designations
24
Comparative US/EU Criterion for Orphan Drug Designation
• Common
• Epidemiological (prevalence)
(7/10.000 US; 5/10000 EU)
• Economic (unlikely to generate sufficient return on
investment)
• Medical plausibility of the condition
• Biological/pharmacological rationale
• Sub-setting (salami-slicing strategy):exceptional
• EU only
• Assumption of significant benefit
• Existing methods are not satisfactory
25
Orphan Medicinal Products in the EU
The Incentives (non exhaustive):
• Market exclusivity
• Protocol assistance during the development, with
involvement of the CPMP
• Access to the Centralized System (independent of List A/B)
• Fee reduction for centralised applications (and marketing
authorisation maintenance activities)
• Priority access to EU research programs
• National incentives (grants, tax reductions)
• SME’s Office (EMEA)
26
Comparative US/EU Incentive
for Orphan Designated Products
• Common
• Market exclusivity rights
• Scientific Advice / Protocol Assistance/ SME’s
• Fee-waivers
• Specific for US
• Tax credit
• FDA grants
• Specific for EU
• Direct access to centralised procedure
• Priority access to EU research programs
• National incentives and measures
27
Orphan Medicinal Products in the EU
• Period of ten years exclusivity from the date of
marketing
• Conditions
orphan designation
AND marketing authorisation throughout EU
• Scope of exclusivity
no market authorisation for similar medicinal products
in the same indication(s)
28
From: REGULATION (EC) No 141/2000
Article 8, Market exclusivity
Where a marketing authorisation in respect of an orphan
medicinal product is granted pursuant to Regulation
(EEC) No 230993.. <cut>.. The Community and the Member
States shall not, for a period of 10 years, accept another
application for a marketing authorisation, or grant a
marketing authorisation or accept an application to
extend an existing marketing authorisation, for the same
therapeutic indication, in respect of a similar medicinal
product.
29
Significant benefit
• Normally in terms of improved efficacy and/or safety and/or
contribution to patient care
• Exceptionally, potential availability can be taken into
account, e.g. A product authorised in all Member States as
opposed to a product authorised only in one or very few
Member States
30
Defining a condition (I)
Exceptionally subsets as valid conditions:
A subset of a (frequent) disease could be considered a valid
condition if patients in that subset present distinct
evaluable characteristic(s) with a plausible link to the
condition and if
– such characteristics are essential for the medicinal
product to carry out its action
– the absence of these characteristics will render the
product ineffective in the rest of the population
31
Defining a condition (II)
Generally invalid subset:
• Different degrees of severity or stages or localization of a
disease
• A subset of patients within a condition in whom the
product is expected to show a favorable benefit/risk
32
The “salami-slicing” and “evergreening” approaches are aimed to:
•
Fragment the population into “artificial” subsets within a
disease/condition
•
To meet the prevalence criteria by creating a “non-true” population
subgroup
•
To benefit from market-exclusivity rights
•
To attempt to lowering usual requirements for the submission of an
application for M.A.
•
To gain additional exclusivity rights by adding subsequent new-nonwell justified target populations (“the evergreening tactic”)
33
Subsetting a medical condition:“salami-slicing strategy”
Total >5/10.000
“Subset” <5/10.000
No
Yes
Prevalence criteria
34
Medically Plausible Subsets (I)
• The true disease process.
• The seriousness of the condition
• The inherent characteristics of the drug
• The mechanism of action of the drug
• Unique characteristics of the patient population
35
Medically Plausible Subsets (II)
Questions to address:
• Is the subset a “real” sub-population?
•
Eg., not a stage of the general disease category?
• Why should the drug be limited to this subset?
•
Are there characteristics of the larger patient population
which exclude them from this treatment?
• Will the drug be useful in the larger population?
• Is the selection criteria in clinical trials acceptable ?
36
ORPHAN DESIGNATION - How to Apply
• Sponsors to notify EMEA of intent to submit at least 2
months prior to filing
• Sponsors are encouraged to request a pre-submission
meeting with EMEA prior to filing
• Co-ordinators (1 COMP, 1 EMEA) and expert(s) will be
appointed
• Applications to be prepared in accordance with Guideline
on Format and Content of Applications for Designation
37
Orphan Medicinal Products in the EU
The procedure
A sponsor submits the application to the EMEA *
the EMEA validates the application (day 1)
the EMEA prepares a summary report
the EMEA COMP adopts an Opinion (by day 90)
the EU Commission adopts a Decision (30 days)
*Pre-submission meetings with EMEA highly encouraged
38
Protocol assistance
•3 Representatives of the COMP are members of the Scientific
Advice Review Group since January 2002.
•They are responsible for the evaluation of Questions related
to significant benefit. In these cases the significant benefit
responses are discussed and adopted by the COMP and the
scientific advice letter is co-signed by the two Chairpersons
39
Dealing with the three possible scenarios for orphan designation
• Non authorised products are available in the EU
• Evidence-based rationale needed
• Existing treatments are available in the EU
• “Assumption of significant benefit” or “Existing
methods are not satisfactory”
• When a designated products holds a community
authorisation
• A “similar” should demonstrate “clinical
superiority” to the existing one
40
Proposed Orphan condition
Redefine
Medical Plausibility
No
No
Yes
Prevalence justification < 5/10.000
Yes
Satisfactory methods
Yes
No
Assumption on Significant benefit
Overall
No
Negative opinion
Yes
Rationale
No
Yes
Designation
41
SUMMARY OF ORPHAN DRUGS
42
Estatus huérfanos Unión Europea - Investigacional
 1085 Solicitudes de designación de medicamento huérfano
 743 Designaciones (90 solicitudes/año)
 Desde 2000 el promedio de éxito es del 72%
 En el último año el porcentaje de solicitudes positivas es del 75 %
 713 Decisión Comisión Europea
 261 Actividades realizadas
 15 negativas
© EMEA (Abril 2000- Febrero 2010)
Status of Orphan Applications
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
Total
No. of
applications
submitted
72
83
80
87
108
118
104
126
119
164
1061
Positive
COMP
Opinions
26
64
43
54
75
88
81
97
86
113
727
Commission
Decisions
14
64
49
55
72
88
80
98
73
106
699
Final
Negative
COMP
Opinions
0
1
3
1
4
0
2
1
1
2
15
Withdrawals
6
(one
awaiting
appeal)
Update 22 February
2010
27
30
41
22
30
20
19
31
23
249
Status of Orphan Applications
2000
Total
No. of
applications
submitted
24
1085
Positive
COMP
Opinions
16
743
Commission
Decisions
14
713
Final
Negative
COMP
Opinions
0
15
Withdrawals
12
261
Update 22 February
2010
Status of Orphan Applications
180
160
140
120
100
80
60
40
20
0
2000
submitted
2002
2004
positive opinions
Update 22 February
2010
2006
2008
negative opinions
2010
withdrawals
Commission decisions
Distribution of Opinions
other
10%
musculoskeletal and
nervous system
12%
metabolism
10%
antiinfectious
3%
immunology
10%
oncology
46%
cardiovascular and
respiratory
9%
immunology
cardiovascular and respiratory
metabolism
other
Update 22 February
2010
oncology
antiinfectious
musculoskeletal and nervous system
Medicamentos Huérfanos designados en la UE (II)
Abril 2000 – Febrero 2010
COMP/EMEA
8%
50%
42%
Medicamentos Huérfanos designados distribuidos por tipo de población (total: 743)
Adult/Paediatric Use (designated)
Adult
42%
Both
50%
Paediatric
8%
Update 22 February
2010
Adult/Paediatric Use (designated)
100%
80%
60%
40%
20%
0%
2000 2001 2002 2003 2004 2005 2006 2007 2008 2009
Medical conditions affecting adults only
Medical conditions affecting both children and adults
Medical conditions affecting children only
Update 22 February
2010
Prevalence Designated Conditions
12%
less than 1 in 10,000
36%
between 1 and 3 in
10,000
more than 3 in 10,000
52%
Update 22 February
2010
Status of Orphan Marketing Authorisation Applications
 59 authorisations granted to date*
 Fabrazyme for Fabry disease
 Replagal for Fabry disease
 Glivec for chronic myeloid leukaemia, ALL, GIST, DFSP,
MDS/MPD and HES/CEL
 Tracleer for pulmonary arterial hypertension,
systemic sclerosis
 Trisenox for acute promyelocytic leukaemia
 Somavert for acromegaly
 Zavesca for Gaucher disease and Niemann-Pick type C disease
 Carbaglu for N-acetylglutamate synthetase deficiency
•2 withdrawn from the register of orphan drugs
cont’d
Update 22 February
2010
Status of Orphan Marketing Authorisation Applications
 59 authorisations granted to date
 Aldurazyme for Mucopolysaccharidosis type I
 Busilvex for haematopoietic progenitor cell transplantation
 Ventavis for pulmonary arterial hypertension
 Onsenal for Familial Adenomatous Polyposis
 Litak for indolent non-Hodgkin’s lymphoma
 Lysodren for adrenal cortical carcinoma
 Pedea for Patent Ductus Arteriosus
 Photobarr for Barret’s oesophagus
 Wilzin for Wilson's disease
 Xagrid for Thrombocythaemia
cont’d
Update 22 February
2010
Status of Orphan Marketing Authorisation Applications
 59 authorisations granted to date
 Orfadin for tyrosinemia type 1
 Prialt for chronic pain requiring intraspinal analgesia
 Xyrem for narcolepsy - withdrawn from the register of orphan drugs
 Revatio for pulmonary arterial hypertension
 Naglazyme for Mucopolysaccharidosis VI or Maroteaux-Lamy
syndrome
 Myozyme for Glycogen Storage Disease type II (Pompe’s disease)
 Evoltra for acute lymphoblastic leukaemia
 Nexavar for renal cell carcinoma and hepatocellular carcinona
cont’d
Update 22 February
2010
Status of Orphan Marketing Authorisation Applications
 59 authorisations granted to date
 Sutent for gastrointestinal stromal tumour and renall cell
carcinoma - withdrawn from the register of orphan drugs
 Savene for anthracycline extravasation
 Thelin pulmonary arterial hypertension
 Exjade for chronic iron overload requiring chelation theraphy
 Sprycel for chronic myeloid leukaemia and acute lymphoblastic
leukaemia
 Inovelon for epilepsy
 Cystadane for homocystinuria
 Elaprase for mucopolysaccharidosis
cont’d
Update 22 February
2010
Status of Orphan Marketing Authorisation Applications
 59 authorisations granted to date









Diacomit for myoclonic epilepsy in infancy
Revlimid for multiple myeloma
Soliris for paroxysmal nocturnal haemoglobinuria
Siklos for sickle cell syndrome
Atriance for acute lymphoblastic leukaemia
Increlex for growth failure
Gliolan for glioma
Yondelis for soft tissue sarcoma, ovarian cancer
Tasigna for chronic myelogenous leukaemia
 Torisel for renal cell carcinoma, mantle cell lymphoma
 Thalidomide Pharmion 50 mg Hard Capsules for myeloma
cont’d
Update 22 February
2010
Status of Orphan Marketing Authorisation Applications
 59 authorisations granted to date
 Volibris for pulmonary arterial hypertension and chronic
thromboembolic pulmonary hypertension
 Firazyr for angioedema
 Ceplene for acute myeloid leukaemia
 Kuvan for hyperphenylalaninemia
 Vidaza for myelodysplastic syndromes, chronic myelomonocytic
leukemia and acute myeloid leukemia
 Nplate for thrombocytopenia
 Mepact for osteosarcoma
 Nymusa for apnoea
 Afinitor for renal cell carcinoma
cont’d
Update 22 February
2010
Status of Orphan Marketing Authorisation Applications
 59 authorisations granted to date





Mozobil for stem cell transplantation
Cayston for cystic fibrosis
Arcalyst for cryopirin-associated periodic syndromes
Ilaris for cryopirin-associated periodic syndromes
Firdapse for Lambert-Eaton myasthenic syndrome
Update 22 February
2010
Status of Orphan Marketing Authorisation
Applications by Therapeutic Field
 59 authorisations granted to date by THERAPEUTIC FIELD *
ONCOLOGY
Acute lymphoblastic leukaemia (ALL)
Evoltra, Glivec, Sprycel, Atriance
Acute myeloid leukaemia
Trisenox, Ceplene, Vidaza
Adrenal cortical carcinoma
Lysodren
Chronic eosinophilic leukaemia (CEL) and the
hypereosinophilic syndrome (HES)
Glivec
Chronic myeloid leukaemia (CML)
Glivec, Sprycel, Tasigna
Update 22 February
2010
cont’d
* 2 withdrawn from the register of orphan drugs
Status of Orphan Marketing Authorisation
Applications by Therapeutic Field
59 authorisations granted to date by THERAPEUTIC FIELD
ONCOLOGY cont’d
Dermafibrosarcoma protuberans (DFSP)
Glivec
Dysplasia in Barrett's Esophagus
Photobarr
Familial Adenomatous Polyposis
Onsenal
Gastrointestinal stromal tumours (GIST)
Glivec, Sutent withdrawn from the register of orphan drugs
Glioma
Gliolan
Update 22 February
2010
cont’d
Status of Orphan Marketing Authorisation
Applications by Therapeutic Field
59 authorisations granted to date by THERAPEUTIC FIELD
ONCOLOGY cont’d
Hairy cell leukaemia
Litak
Hepatocellular carcinoma
Nexavar
Mantle cell Lymphoma
Torisel
Osteosarcoma
Mepact
Ovarian cancer
Yondelis
Update 22 February
2010
cont’d
Status of Orphan Marketing Authorisation
Applications by Therapeutic Field
59 authorisations granted to date by THERAPEUTIC FIELD
ONCOLOGY cont’d
Renal cell carcinoma
Nexavar, Sutent withdrawn from the register of orphan drugs, Torisel, Afinitor
Soft tissue sarcoma (STS)
Yondelis
Update 22 February
2010
Status of Orphan Marketing Authorisation
Applications by Therapeutic Field
59 authorisations granted to date by THERAPEUTIC FIELD
ENDOCRINO/METABOLISM
Acromegaly
Somavert
Fabry disease
Fabrazyme, Replagal
Gaucher disease
Zavesca
Glycogen Storage Disease
Myozyme
Growth factor-1 deficiency
Increlex
Update 22 February
2010
cont’d
Status of Orphan Marketing Authorisation
Applications by Therapeutic Field - cont’d
59 authorisations granted to date by THERAPEUTIC FIELD
ENDOCRINO/METABOLISM cont’d
Homocystinuria
Cystadane
Hyperphenylalaninemia
Kuvan
Mucopolysaccharidosis
Aldurazyme, Elaprase, Naglazyme
N-acetylglutamate synthetase deficiency
Carbaglu
Niemann-Pick type C disease
Zavesca
Update 22 February
2010
cont’d
Status of Orphan Marketing Authorisation
Applications by Therapeutic Field
59 authorisations granted to date by THERAPEUTIC FIELD
ENDOCRINO/METABOLISM cont’d
Tyrosinaemia
Orfadin
Wilson's disease
Wilzin
HAEMATOLOGY
Essential thrombocythaemia
Xagrid
Haematopoietic cell transplantation
Busilvex
Haemoglobinuria
Soliris
Update 22 February
2010
cont’d
Status of Orphan Marketing Authorisation
Applications by Therapeutic Field
59 authorisations granted to date by THERAPEUTIC FIELD
HAEMATOLOGY cont’d
Iron overload
Exjade
Multiple myeloma (MM)
Revlimid, Thalidomide Pharmion 50 mg Hard Capsules
Myelodysplastic/myeloproliferative diseases (MDS/MPD)
Glivec, Vidaza
Sickle cell syndrome
Siklos
Thrombocytopenia
Nplate
Stem cell transplantation
Mozobil
Update 22 February
2010
cont’d
Status of Orphan Marketing Authorisation
Applications by Therapeutic Field
59 authorisations granted to date by THERAPEUTIC FIELD
CARDIOVASCULAR AND RESPIRATORY
Patent ductus arteriosus
Pedea
Pulmonary arterial hypertension (PAH)
Tracleer, Ventavis, Revatio, Thelin
Pulmonary arterial hypertension and chronic thromboembolic
pulmonary hypertension
Volibris
Apnoea
Nymusa
Cystic fibrosis
Cayston
Update 22 February
2010
cont’d
Status of Orphan Marketing Authorisation
Applications by Therapeutic Field
59 authorisations granted to date by THERAPEUTIC FIELD
NERVOUS SYSTEM
Epilepsy
Diacomit, Inovelon
Narcolepsy
Xyrem withdrawn from the register of orphan drugs
Pain
Prialt
Lambert-Eaton myasthenic syndrome
Firdapse
cont’d
Update 22 February
2010
Status of Orphan Marketing Authorisation
Applications by Therapeutic Field
59 authorisations granted to date by THERAPEUTIC FIELD
OTHER
Systemic sclerosis (scleroderma)
Tracleer
Anthracycline extravasations
Savene
Angioedema
Firazyr
Cryopirin-associated periodic syndromes
Arcalyst, Ilaris
Update 22 February
2010
Status of Orphan
Marketing Authorisation Applications
 Adopted positive opinion
 Tepadina for haematopoietic progenitor cell transplantation
 Revolade for idiopathic thrombocytopenic purpura
 Arzerra for chronic lymphocytic leukaemia
 Ongoing applications in review process
 12 centralised applications in review process
 Variations / Line Extensions in review process
 Negative outcomes for orphan MAA
 34 applications for MA withdrawn
 6 negative decisions/refusals
Update 22 February
2010
Distribution of Orphan MAAs
59 orphan authorised by centralised MA*
12%
3%
39%
10%
14%
22%
antineoplastic and immunomodulating agents
blood
cardiovascular
metabolism
musculoskeletal and nervous system
others
*2 withdrawn from the register of orphan drugs
Update 22 February
2010
©European Medicines Agency 2010.
Reproduction and/or distribution of this document
is possible for non-commercial purposes provided
that EMEA is always acknowledged as the source
in each copy. Citations may be made, provided
the source is always acknowledged. See:
http://www.emea.europa.eu/htms/technical/dmp/c
opyritel.htm
Update 22 February
2010
Common deficiencies for ODD refusal
1) Scientific rational (Proof of Concept) weak, inconsistent or poorly
justified (40%)
2) Prevalence figures based on inappropriate epidemiological data (59%)
3) Lack of medically plausible target population (artificial subsetting) (41%)
4) Inaccurate search of existing authorised methods for the orphan
condition
5) Assumptions on significant benefit not credible or not well-substantiated
(42%)
A “dream” is not enough for designation
73
APPROVAL UNDER: EXCEPTIONAL CIRCUMSTANCES
or CONDITIONAL APPROVAL
 Limited clinical data available because:
 rare disease (“orphan disease”)
 current scientific knowledge does not allow a
comprehensive assessment
 ethical constraints in performing conventional RCT
 “Specific Obligations” (i.e. Clinical studies) should be carried out
within an agreed timeframe
 Annual re-assessment of the benefit/risk ratio by the CHMP
 The SPC should contain this information
74
Some hurdles on Orphan Medicines Clinical Research (I)
• Lack of public awareness (“Invisible diseases”)
• Scarcity of Clinical Experts and Reference Centres
• Delays on Diagnosis (Genetic Testing / Neonatal screening)
• Small size population
• Geographic dispersion
• Life-threatening /chronic debilitating conditions
• Heterogeneous conditions
• Difficult to stratify by stage/severity
• Limited available treatments
75
Some hurdles on Orphan Medicines Clinical Research (II)
• Lack of validated biomarkers and surrogate endpoints
• Lack of predictive/validated preclinical models
• Ethical concerns on the use of placebo (e.g. Emerging
therapies) and vulnerable population
• Off-label use (medicines for children)
• Participative role of patients to be increased
• Poorly motivated health professionals/investigators
• Lack of information to “care-givers”
• Excessive bureaucratic/administrative barriers
76
Challenges on Orphan Drug Clinical Development (“Feasibility Concept”)
• Conventional methodological designs need to be adjusted and
applied in a flexible manner
• Alternative methodological approaches and patient-saving
designs should be encouraged
• Compassionate and expanded access programs should not
undermined the conduct of well-designed studies
• Investigation phase goes beyond the MA: conditional / under
exceptional circumstances approval, thus early PhV planning
and risk-management strategies becomes crucial
« Nice to know v.s. Need to know »
77
Types of Clinical Studies of Orphan Drugs approved by DOPD/FDA AND
EMEA*
Division of Oncologic Drug Products / FDA
Centrally authorised / EMEA
(10 products)
(22 products)
29%
71%
Alternative methodologies
Double blinded randomised CT
* From 2nd Eurordis workshop, July 2005
78
List of Drugs Approved by DODP
Drug (Year of
Approval)
Indication
Number of
“Pivotal”
Studies
Patients
Clofarabine (’04)
Relapsed or refractory ALL
2
66
Tositumomab (’01)
CD20+ follicular NHL
5
230
Alitretinoin (’99)
Kaposi sarcoma
2
350
Bortezomid (’03)
Progressive multiple myeloma
2
256
Imatinib (’02)
CD117+ unresectable GIST
1
147
Pemetrexed (’04)
Metastatic malignant mesotheliona
1
448
Doxorubicin (’99)
Refractory metastatic ovarian cancer
4
650
Gemtuzumab
ozogamicin (’00)
CD33+ acute myelocytic leukemia
3
277
Carmustine (’96)
Recurrent glioblastoma multiforme
1
222
Alemtuzumab (’01)
Chronic lymphocytic leukemia
3
149
79
Overview clinical studies in positive opinions
Main (n)
Phase
Fabrazyme
1
III
DB, R, Pbo, Mc
Replagal
2
II
DB, R, Pbo, Uc
Tracleer
2
II, III
DB, R, Pbo, Mc
Somavert
1
III
DB, R, Pbo, Mc
Aldurazyme
1
III
DB, R, Pbo, Mc
Ventavis
1
III
DB, R, Pbo, Mc
Onsenal
1
II
DB, R, Pbo, Mc
Prialt
3
II-III
DB, R, Pbo, Mc
Xyrem
2
III
DB, R, Pbo, Mc
Pedea
Mixed
-
Metaanalysis (6 studies)
1
Phase III
Partially blinded (biopsy
evaluation), R (2:1), Mc
Photobarr
Design
80
Overview clinical studies in positive opinions
Main (n)
Phase
2
II
O, NR, Mc
3 (1x3)
1
II
II
O, NR, NC, Mc
(DB), R, 2 doses, Mc
Trisenox
2
I-II, II
Zavesca
1
I-II
Orfadin
1
Litak
1
II
O, NR, Mc
Busilvex
2
II
O, NR, NC, Mc
Xagrid
Glivec CML
Glivec GIST
Design
O, NR, NC, Uc-Mc
O, NR, NC, Mc
Compassio O, Mc
nate use
81
Overview clinical studies in positive opinions (I)
Efficacy Patients
Safety patients
Fabrazyme
58
73
Replagal
41
43
Glivec CML
Myeloid blast crisis, n=260
Accelerated phase, n=235
Chronic phase, n=532
1176
Glivec GIST
147
147
Trisenox
52
251
Tracleer
246
174
Zavesca
82
96
Somavert
157
167
Carbaglu
12
20
Busilvex
102
103
Aldurazyme
45
55
82
Overview clinical studies in positive opinions (II)
Efficacy Patients
Safety patients
Ventavis
203
279
Xagrid*
316
(+ 242 compassionate)
>4600
Onsenal
83
83
Litak
63
523
Photobarr
208
324
Lysodren
1064, bibliographic
>2000
Pedea
429 metaanalysis
986
Wilzin
191 bibliographic
255
83
Exposure (5/10,000 = 227,500 patients in EU)*
Efficacy
Patients
Population affected
(000 EU)
Prev
Fabrazyme
58
 5,000-10,000
0.13-0.27
Replagal
41
 5,000-10,000
0.13-0.27
Glivec (CML)
1027
 34,000
0.9
Trisenox
52
 30,000
0.8
Tracleer
246
 36,000
0.95
Zavesca
92
 22,600 (*1060)
0.6
Somavert
157
 22,600
0.6
Carbaglu
12
 50
0.00125
Gilvec (GIST)
147
 2,200
0.06
84
BE AWARE OF...
Randomised clinical trials are the gold standard for investigating and
confirming clinical safety and efficacy of new medicinal products ...
but
... the evidence indicates that the benefit/risk profile is driving the orphan drug
approval when there are difficulties to perform conventional prospective
randomised trials
(Some) rare conditions may need alternative methodological and statistical
considerations without compromising efficacy and/or undermining safety
EMEA guideline for the conduct of clinical investigations in
small sized populations (adopted, February 2006)
85
The patient’s perspective:
Why collaborate in clinical trials?
Sponsors
Research
Disease
Experts
Clinical
trials
Actors
Patients
Market
Treatments
Users
86
When to collaborate in clinical trials?
Protocole
On-going
Discussion
of results
Conclusions
Constructive
Collaboration
Criticism
Agreement
«It is
possible»
«It is
stimulating»
«It is
desirable»
87
The increasing complex environment of clinicians
Funding
Research Bodies
Regulatory
Authorities
Industry
ERC
Primary Care
Clinical
Individuals Families
General Hospitals
Researcher
Patients
Organization
Teaching Hospitals
Supportive
Team
NHS
Pharmaceutical Policy
Learned
Societies
Academic Liaisons
Ethical Care Bodies
ERC: Ethic Review Committees
88
Rare Diseases’ Action Lines (I)
TRAINING
CONTINUING PROFESSIONAL DEVELOPMENT
BIOMEDICAL
EPIDEMIOLOGICAL
RESEARCH
Professionals
patients
Public-private
Partenariat
Pharmaceutical
Industry
INFORMATION
QUALITATIVE AND SOCIAL RESEARCH
89
Rare Diseases’ Action Lines (II)
REFERENCE CENTERS
EXPERTISE/SPECIALIZED HOSPITALS
HEALTH AND SOCIAL SERVICES
PATIENTS’ MOBILITY
Experts’ Network
Fostering Social Care
PRIMARY CARE/
HOME HELP
DEPENDENCY AND DISABILITY
90
Rare Diseases’ Action Lines (III)
HEALTH INTERVENTIONS/
GENETIC DIAGNOSE
FAMILY SUPPORT
AND
SPECIAL EDUCATION
Timely and equity
access
Promoting
Autonomy
THERAPEUTIC
INTERVENTIONS
WORK FACILITIES AND LABOR ENVIRONMENT
91
Rare Diseases’ Action Lines (IV)
EU Advisory Agency
OEER
BEST PRACTICES
EU CONFERENCES
EU BUDGET
EU/National
and
Regional
Co-ordination
Health Indicators
RESEARCH, TRAINING, EXPERTS
NATIONAL BUDGETS
92
DOCUMENTOS DE REFERENCIA
•
Comunicación de la Comisión Europea (GD Sanco, 2008): Las
enfermedades raras: un desafío para Europa. Comisión Europea
•
Recomendación del Consejo, 2009
•
Senado: Ponencia de Estudio de ER, 23 febrero 2007
•
Plan Nacional de Enfermedades Raras 20 junio 2009
Plan Nacional Francés de ER 2004-2008
93
Recent Spanish contribution to foster
Orphan Drug Research for Rare Diseases (I)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Priority for pricing and reimbursement (Dirección General de Farmacia)
New decree for compassionate and extended use (AEMPS)
Scientific Advice for Clinical Investigations (AEMPS)
CIBER for Rare Diseases Research (Instituto de Salud Carlos III)
Burgos National Center (Ministerio de Asuntos Sociales)
Decree for establishing references centers (Ministerio de Sanidad)
Call for funding independent clinical research (January 2007/20ME,
DGF/AEMPS)
Report and recommendations from the Spanish Senate (February 2007)
Priority for several Spanish-based pharmaceutical industries
(Farmaindustria / Plan Profarma, Ministerio de Industria)
Disabilities and Social Help (Ley de Dependencia)
94
Recent Spanish contribution to foster
Orphan Drug Research for Rare Diseases (II)
11.
National Health Care System: Plan Nacional de Enfermedades Raras (June
2009)
11.
Several actions at autonomous and regional level: Cataluña
–
–
–
–
Propuesta de resolución sobre enfermedades raras; Parlamento de Cataluña.
Tram 250/01182-08; Butlletí Oficial del Parlament de Catalunya; 31 julio 2008;
Núm. 312;
Generalitat de Catalunya; creación de la Comisión Asesora en Enfermedades
Raras (CAMM) (mayo 2009)
La Marató de TV3 año 2009 Enfermedades Raras
Generalitat de Catalunya; creación de la Comisión de Acceso a Terapias
Complejas (CATFAC) (febrero 2010)
95
Benefits of EU Orphan Medicines Regulation
 Awareness activities growing
 Positive impact on SME’s
 Increasing innovative medicines: paving the road for the
entrance of emerging therapies
 Facilitating liaison of reference health/research centres
 Openness of Public Clinical Trials Database
 Better understanding of patient’s needs
 Progressive prioritisation of RD on public health agendas
96
….But ……
…….Much still remains to be done………
 Ensuring availability/access to OMP for all patients
 Warranting affordability and long-term sustainability
 Global approach and more inter-regional cross-collaboration
 Better epidemiological knowledge of many rare conditions
 Developing appropriate methodological / statistical patient-saving
approaches
 Strengthen early pharmacovigilance planning and risk management
strategies
 Increasing public funding from UE/national institutions
 More and better co-ordination of National Incentives
97
So….. Rare Diseases offers…..
• An unique and challenging clinical paradigm
• Encompasses a wide range of different medical conditions
• Knowledge gather in this setting can be extrapolated in other
conventional diseases
• High contribution from patients organisations
• Stimulates creativity and interest of clinicians and academics
• Big-pharma and SMEs may use this opportunity to further
develop “personalised” medicines
98
Creating a true EU partnering environment with all stake-holders
Rare (low-prevalence) diseases
are a pan-European challenge
that need national solutions
…also…
Rare conditions are a national
problem that need EU strong
support and policy commitment
99