1 Rare Diseases and Orphan Medicinal Products Máster en diagnóstico y terapia de las enfermedades raras Josep Torrent-Farnell Universitat Autònoma de Barcelona

1

Rare Diseases and Orphan Medicinal Products

Máster en diagnóstico y terapia de las enfermedades raras

Josep Torrent-FarnellUniversitat Autònoma de Barcelona

Hospital de la Santa Creu i Sant PauComité de Medicamentos Huérfanos, EMEA, Londres

22 marzo 2010Universidad Internacional de Andalucía

2

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)

3

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

4

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

5

• 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

Some facts on rare diseases (III)

6

• 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).

Some facts on rare diseases (IV)

7

Orphan conditions (RD) vs neglected diseases

• Neglected diseases are medical conditions (severe, life-threatening 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.

8

Some examples of Rare Diseases*

• Hodgking and non-Hodgking Lymphomas

• All types of Leukemias

• More than 400 solid cancers conditions

• Multiple Mieloma

• Sarcoidosis

• Graft-versus-Host Diseases

• Duchene Muscular Distrophy

• Friedreich Ataxia

• Leber Hereditary Optic Neurophaty (LHON)

• Laron Syndrome

* NORD, EURORDIS, ORPHANET, databases

• ELA

• Pompe Disease

• Nieman-Pick-Disease

• Gaucher Disease

• Fabry Disease

• Polyarteritis Nodosa

• Mucopolysaccharidosis

• Thalasemias

• Ewing Sarcoma

• Churg-Strauss Syndrome

9

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

10

Unmet medical needs for patients affected by rare disorders require global and international joint efforts

11

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

12

Orphan Medicinal Products in the EUInternational Comparison

Europe Orphan Regulation 2000

-< 185000 Patients, less than 5/10000 Inhabitants

USA Orphan Drug Act 1983

-< 200000 Patients, 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

13

Comparative Requirements for ODD

US EU

Epidemiological “prevalence”

Nature of disease

6.8 / 10,000

Rare

5 / 10,000

Life-threatening,debilitating

Scientific rationale YES YES

Economic (lack of ROI) YES YES

Significant benefit (added therapeutic value)

“Medically plausible” subset

Time of application

Medical devices

NO

YES

Before MA

Humanitarian use

YES

YES

Before MA

NO

14

Comparative Requirements for ODD

US EU

Market exclusivity (yrs) 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)

Tax credits YES (50% of clinical cost) Depends on MS

15

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

16

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

17

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)

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• 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

Some basic considerations (I):

Designation

19

• 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

Some basic considerations (II):

Marketing authorizations

20

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

21

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)

22

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

23

EMEACOMP

EU Panel

Experts

rare

diseases

CHMP

Marketing Authorisation

‘Entry Level’ ‘Outcome’

Review

Applications

Designation

Advice on designation Protocol Assistance Scientific Advice

Review

Applications

24

• 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

Orphan Designation Criteria

25

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

26

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)

27

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

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• Period of ten years exclusivity from the date of marketing

• Conditionsorphan designationAND marketing authorisation throughout EU

• Scope of exclusivity no market authorisation for similar medicinal products

in the same indication(s)

29

From: REGULATION (EC) No 141/2000Article 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.

30

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

31

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

32

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

33

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-non-

well justified target populations (“the evergreening tactic”)

34

Subsetting a medical condition:“salami-slicing strategy”

Total >5/10.000 “Subset” <5/10.000

Prevalence criteria

No Yes

35

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

36

Medically Plausible Subsets (II)

• 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 ?

Questions to address:

37

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

38


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

39

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

40

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

41

Proposed Orphan condition

Prevalence justification < 5/10.000No Yes

Satisfactory methods

Yes No

Negative opinion

Overall

Rationale

Designation

Assumption on Significant benefit

No Yes

No Yes

Medical Plausibility

YesNo

Redefine

42

SUMMARY OF ORPHAN DRUGS

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)

Update 22 February 2010 ©European Medicines Agency

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 (one

awaiting appeal)

15

Withdrawals 6 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


0

20

40

60

80

100

120

140

160

180

2000 2002 2004 2006 2008 2010

submitted positive opinions negative opinions withdrawals Commission decisions

Status of Orphan Applications


Distribution of Opinions

immunology10%

oncology46%antiinfectious

3%

musculoskeletal and nervous system

12%

other10%

metabolism10%

cardiovascular and respiratory

9%

immunology oncologycardiovascular and respiratory antiinfectiousmetabolism musculoskeletal and nervous systemother

8% 50% 42% Medicamentos Huérfanos designados distribuidos por tipo de población (total: 743)

Medicamentos Huérfanos designados en la UE (II) Abril 2000 – Febrero 2010

COMP/EMEA


Adult/Paediatric Use (designated)

Adult42%

Paediatric8%

Both50%


0%

20%

40%

60%

80%

100%

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

Adult/Paediatric Use (designated)


Prevalence Designated Conditions

36%

52%

12%less than 1 in 10,000

between 1 and 3 in10,000

more than 3 in 10,000


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

59 authorisations granted to date*

cont’d

Status of Orphan Marketing Authorisation Applications


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

59 authorisations granted to date

cont’d



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

Status of Orphan Marketing Authorisation Applications 59 authorisations granted to date

cont’d


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


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


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


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

59 authorisations granted to dateStatus of Orphan Marketing Authorisation Applications


59 authorisations granted to date by THERAPEUTIC FIELD * ONCOLOGY

Acute lymphoblastic leukaemia (ALL)Evoltra, Glivec, Sprycel, Atriance

Acute myeloid leukaemiaTrisenox, Ceplene, Vidaza

Adrenal cortical carcinomaLysodren

Chronic eosinophilic leukaemia (CEL) and the hypereosinophilic syndrome (HES)

Glivec

Chronic myeloid leukaemia (CML)Glivec, Sprycel, Tasigna * 2 withdrawn from the register of orphan drugs

Status of Orphan Marketing Authorisation Applications by Therapeutic Field

cont’d


59 authorisations granted to date by THERAPEUTIC FIELD

ONCOLOGY cont’d

Dermafibrosarcoma protuberans (DFSP)Glivec

Dysplasia in Barrett's EsophagusPhotobarr

Familial Adenomatous PolyposisOnsenal

Gastrointestinal stromal tumours (GIST)Glivec, Sutent withdrawn from the register of orphan drugs

GliomaGliolan


cont’d



ONCOLOGY cont’d

Hairy cell leukaemiaLitak

Hepatocellular carcinomaNexavar

Mantle cell LymphomaTorisel

OsteosarcomaMepact

Ovarian cancerYondelis


cont’d



ONCOLOGY cont’d

Renal cell carcinomaNexavar, Sutent withdrawn from the register of orphan drugs, Torisel, Afinitor

Soft tissue sarcoma (STS)Yondelis





ENDOCRINO/METABOLISM

AcromegalySomavert

Fabry diseaseFabrazyme, Replagal

Gaucher diseaseZavesca

Glycogen Storage DiseaseMyozyme

Growth factor-1 deficiencyIncrelex cont’d


Status of Orphan Marketing Authorisation Applications by Therapeutic Field - cont’d


ENDOCRINO/METABOLISM cont’d

HomocystinuriaCystadane

HyperphenylalaninemiaKuvan

MucopolysaccharidosisAldurazyme, Elaprase, Naglazyme

N-acetylglutamate synthetase deficiencyCarbaglu

Niemann-Pick type C disease

Zavesca cont’d



59 authorisations granted to date by THERAPEUTIC FIELD ENDOCRINO/METABOLISM cont’d

TyrosinaemiaOrfadin

Wilson's diseaseWilzin

HAEMATOLOGY

Essential thrombocythaemiaXagrid

Haematopoietic cell transplantationBusilvex

Haemoglobinuria Soliris cont’d



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 syndromeSiklos

ThrombocytopeniaNplate

Stem cell transplantationMozobil cont’d



CARDIOVASCULAR AND RESPIRATORY

Patent ductus arteriosusPedea

Pulmonary arterial hypertension (PAH)Tracleer, Ventavis, Revatio, Thelin

Pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

VolibrisApnoea

Nymusa

Cystic fibrosisCayston


cont’d



NERVOUS SYSTEM

EpilepsyDiacomit, Inovelon

NarcolepsyXyrem withdrawn from the register of orphan drugs

PainPrialt

Lambert-Eaton myasthenic syndromeFirdapse


cont’d




OTHER

Systemic sclerosis (scleroderma)Tracleer

Anthracycline extravasationsSavene

Angioedema Firazyr

Cryopirin-associated periodic syndromesArcalyst, Ilaris


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



Distribution of Orphan MAAs

39%

22%

10%

12% 3%

14%

antineoplastic and immunomodulating agents metabolismblood musculoskeletal and nervous systemcardiovascular others

59 orphan authorised by centralised MA*

*2 withdrawn from the register of orphan drugs


©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/copyritel.htm

http://www.emea.europa.eu/htms/technical/dmp/copyritel.htm

http://www.emea.europa.eu/htms/technical/dmp/copyritel.htm

73

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

74

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

75

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

76

• 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

Some hurdles on Orphan Medicines Clinical Research (II)

77

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 »

78

Types of Clinical Studies of Orphan Drugs approved by DOPD/FDA AND EMEA*

71%

29%

Division of Oncologic Drug Products / FDA

(10 products)

Alternative methodologies

Double blinded randomised CT

Centrally authorised / EMEA

(22 products)

* From 2nd Eurordis workshop, July 2005

79

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

80

Overview clinical studies in positive opinions

Main (n) Phase Design

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)

Photobarr 1 Phase III Partially blinded (biopsy evaluation), R (2:1), Mc

81

Main (n) Phase Design

Xagrid 2 II O, NR, Mc

Glivec CMLGlivec GIST

3 (1x3)1

IIII

O, NR, NC, Mc (DB), R, 2 doses, Mc

Trisenox 2 I-II, II O, NR, NC, Uc-Mc

Zavesca 1 I-II O, NR, NC, Mc

Orfadin 1 Compassionate use

O, Mc

Litak 1 II O, NR, Mc

Busilvex 2 II O, NR, NC, Mc

Overview clinical studies in positive opinions

82

Overview clinical studies in positive opinions (I)

Efficacy Patients Safety patients

Fabrazyme 58 73

Replagal 41 43

Glivec CML

Glivec GIST

Myeloid blast crisis, n=260Accelerated phase, n=235

Chronic phase, n=532

147

1176

147

Trisenox 52 251

Tracleer 246 174

Zavesca 82 96

Somavert 157 167

Carbaglu 12 20

Busilvex 102 103

Aldurazyme 45 55

83

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

Overview clinical studies in positive opinions (II)

84

Exposure (5/10,000 = 227,500 patients in EU)*

0.00125 5012Carbaglu

0.6 22,600157Somavert

0.06 2,200147Gilvec (GIST)

0.6 22,600 (*1060)92Zavesca

0.95 36,000246Tracleer

0.8 30,00052Trisenox

0.9 34,0001027Glivec (CML)

0.13-0.27 5,000-10,00041Replagal

0.13-0.27 5,000-10,00058Fabrazyme

PrevPopulation affected (000 EU)

Efficacy Patients

85

BE AWARE OF...

... the evidence indicates that the benefit/risk profile is driving the orphan drug approval when there are difficulties to perform conventional prospective randomised trials

Randomised clinical trials are the gold standard for investigating and confirming clinical safety and efficacy of new medicinal products ...

but

(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 insmall sized populations (adopted, February 2006)

86

Patients

The patient’s perspective:Why collaborate in clinical trials?

Clinical trials

Disease Treatments

Experts Actors Users

Research Market

Sponsors

87

When to collaborate in clinical trials?

Protocole On-goingDiscussion of results

Constructive Collaboration Criticism Agreemen

t

«It is possible»

«It is stimulating

»

«It is desirable»

Conclusions

88

Clinical

Researcher

Individuals Families

Patients Organization

Learned Societies

Supportive

Team NHS

Pharmaceutical Policy

IndustryRegulatory Authorities

Primary Care

General Hospitals

Teaching Hospitals

Academic Liaisons

ERC

The increasing complex environment of clinicians

Funding Research Bodies

Ethical Care Bodies

ERC: Ethic Review Committees

89

TRAININGCONTINUING PROFESSIONAL DEVELOPMENT

Professionalspatients

INFORMATION

BIOMEDICAL EPIDEMIOLOGICAL

RESEARCH

Public-privatePartenariat

PharmaceuticalIndustry

QUALITATIVE AND SOCIAL RESEARCH

Rare Diseases’ Action Lines (I)

90

REFERENCE CENTERS EXPERTISE/SPECIALIZED HOSPITALS

Experts’ Network

PRIMARY CARE/HOME HELP

HEALTH AND SOCIAL SERVICESPATIENTS’ MOBILITY

Fostering Social Care

DEPENDENCY AND DISABILITY

Rare Diseases’ Action Lines (II)

91

HEALTH INTERVENTIONS/GENETIC DIAGNOSE

Timely and equity access

THERAPEUTICINTERVENTIONS

FAMILY SUPPORTAND

SPECIAL EDUCATION

PromotingAutonomy

WORK FACILITIES AND LABOR ENVIRONMENT

Rare Diseases’ Action Lines (III)

92

EU Advisory AgencyOEER

EU/National and

Regional Co-ordination

RESEARCH, TRAINING, EXPERTS

BEST PRACTICESEU CONFERENCES

EU BUDGET

Health Indicators

NATIONAL BUDGETS

Rare Diseases’ Action Lines (IV)

93

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

94

Recent Spanish contribution to foster Orphan Drug Research for Rare Diseases (I)

1. Priority for pricing and reimbursement (Dirección General de Farmacia)2. New decree for compassionate and extended use (AEMPS)3. Scientific Advice for Clinical Investigations (AEMPS)4. CIBER for Rare Diseases Research (Instituto de Salud Carlos III)5. Burgos National Center (Ministerio de Asuntos Sociales)6. Decree for establishing references centers (Ministerio de Sanidad)7. Call for funding independent clinical research (January 2007/20ME,

DGF/AEMPS)8. Report and recommendations from the Spanish Senate (February 2007)9. Priority for several Spanish-based pharmaceutical industries

(Farmaindustria / Plan Profarma, Ministerio de Industria)10. Disabilities and Social Help (Ley de Dependencia)

95

Recent Spanish contribution to foster Orphan Drug Research for Rare Diseases (II)

11. National Health Care System: Plan Nacional de Enfermedades Raras (June 2009)

12. 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)

96

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

….But ……

Benefits of EU Orphan Medicines Regulation

97

…….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

98

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

99

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

Documents

1 Rare Diseases and Orphan Medicinal Products Máster en diagnóstico y terapia de las enfermedades raras Josep Torrent-Farnell Universitat Autònoma de Barcelona