Enfermedad minoritaria, terapias nuevas. Una patología que afecta a menos de cinco personas por cada 10.000 habitantes es considerada una enfermedad rara o minoritaria. 35 millones de europeos se ven afectados por alguna de ellas. El 80% son de origen genético y conseguir un diagnóstico rápido es vital para asegurar la calidad de vida futura. La clave, una vez más, es apostar y potenciar la investigación biomédica. Se revisarán los resultados obtenidos los últimos 14 años, en el marco científico y regulador impulsado por la UE desde el año 2000. Sin embargo, se analizarán las dificultades y oportunidades para impulsar la investigación traslacional en estas enfermedades. Sigue la presentación en Youtube: https://www.youtube.com/watch?v=d4U4a8xFCzA&

1. Malalties Minoritàries i Medicaments Orfes
en l'Unió Europea: Reptes i Oportunitats per
la recerca biomèdica
Cicle de Seminaris sobre Malalties Rares
15 d’Octubre de 2014
Josep Torrent-Farnell
Committe Orphan Medicinal Products (COMP/EMA) London
IRDiRC Therapies Scientific Committe
Universitat Autònoma de Barcelona

2. Research and
Innovation
Rare diseases: a challenge too big to be
mastered alone
• Huge unmet medical
needs for patients
across the globe
• Small patient
populations
• Scarce and scattered
research resources and
expertise
©yuriibezrukov/Fotolia.com

3. Research and
Innovation
Acquiring knowledge about genes and Rare
Disease Phenotypes
Source: Kym Boycott 2014

4. 4
What is an orphan drug?
• Drugs aimed to treat diseases which a
prevalence figure lower than 5 cases per 10,000
habitants.
• These includes vaccines, curative treatments,
preventives therapies and diagnostic agents.
• Does not include dietetic measures neither
medical devices.
European Regulation EC No 141/2000

5. 5
Unmet medical needs for rare diseases require worldwide
joint efforts and policies to develop new orphan therapies

6. 6
Orphan regulatory overview
• Sharing same objectives
• Similar incentives and criteria
BUT
• Different prevalence limits
• “Significant Benefit” criterion mandatory only for EU applications
1983 2000

7. 7
Why Rare Diseases and Orphan Drug Development can be
an opportunity for researchers?
• Rare diseases present a lot of unmet medical needs that should be faced up
and embrace more than 7000 multisystemic rare conditions.
• Orphan drug development (from bench-to-bed): opportunity for
translational biomedical research
• There is a regulatory framework that foster and help the research in orphan
drug development and it is coupled with a funding strategy by IRDiRC.
• Orphan drug designation by COMP (EMA) attracts innovation and could be
a tool for researchers institutions to push their research line projects and to
bring new therapies for the sake of patients and social benefit.

8. 8
Orhan designation as a regulatory pathway
• COMP
• Investigational
• Incentives
• Medical condition
 CHMP
 EU Licensing
 Benefit/Risc, Post-Marketing
 Conditional Aproval
 Therapeutic indication
“OUTCOME”
COMP
Review
(P, SB)
DESIGNATION
MARKETING
AUTHORISATION
“GATE OPENER”
“MARKET ACCESS”

9. 9
Main features of orphan designation
• Aimed to human medicines.
• Free procedure.
• Can be applied in any stage of drug development.
• Applicant can be an enterprise, academic institution or individual
• Settled on European Community (EU, Ice, Liech, Nor)
• European Commission Decision gives right to receive incentives
• Evaluation to obtain OD designation follows a non-stop clock 90 days procedure

10. 10
European Criteria for Orphan Designation
• Rarity (lower than 5 cases per 10,000)
• Severity (chronically debilitating or life-threatening)
• Absence of alternative treatment / Significant Benefit
• Medical plausibility (scientific rationale)
• Overall orphan drug Development

11. 11
Incentives
• Economic / Marketing conditions
• Reduction / waiving fees
• Marketing exclusivity in the UE for 10+2 yrs
• Drug development
• Protocol assistance
• National incentives (Member States)
• Priority in EU research programs (DG Research: Horizon 2020)
• Fostering Rare Disease care and policies to facilitate access to
new diagnosis and therapies (DG Sanco: EUCERD)

12. 12
The European Medicines Agency
www.ema.europa.eu
The Committee for Orphan Medicinal Products
(COMP) is responsible for:
• Assessment of orphan drug applications
• Participation on Protocol Assistance
• Assessment on the maintenance orphan
criteria at the time of marketing
authorization
• Collaboration with other EU institutions and
FDA on regular basis

13. 13
CHMP
(Committee for Human Medicinal Products)
CVMP
(Committee for Veternary Medicinal Products)
HMPC
(Committee for Herbal Medicinal Products)
COMP
(Committee for Orphan Medicinal Products)
CAT
(Committee for Advanced Therapy Medicinal Products)
PDCO
(Paediatric Committee)
PRAC
(PhVig Risk Assessment Committee )
EMA Scientific Committees

14. 14
COMP
Composition:
• Chair and Vice Chair
• 1 member/MS
• 3 patient reps
• 3 EMA reps
 Experts and patients
invited
 COMP meets regularly
3 days monthly

15. 15
COMP/EMA: Orphan drug designation
achievements

16. 16
OD by therapeutic field
13%
13%
4%
8%
30%
18%
14%
musculoskeletal&
nervous system
Metabolism
Anti-infectious
Cardiovascular &
respiratory
Oncology
Haematology
Other

17. 17
Orphan designations
• By prevalence:
• More 3 cases per 10.000: 12%
• Between 3 and 1 cases per 10.000: 52%
• Less than 1 cases per 10.000: 36%
• By age:
• Adult only: 42%
• Adult and pediatric: 50%
• Pediatric only: 8%

18. 18
Orphan Drug Designations: Spanish sponsorships (from
April 2000 to September 2014)
Advanced Medical Projects - Spain 1
Advancell - Advanced In Vitro Cell Technologies S.A. - Spain 2
Almirall S.A. - Spain 1
Bioncotech Therapeutics, S.L. - Spain 1
Bionure Farma SL - Spain 1
Centro de Investigación Biomédica en Red (CIBER) - Spain 2
Consejo Superior de Investigaciones Cientificas (CSIC) - Spain 1
Digna Biotech S.L. - Spain 4
Diomune S.L. - Spain 1
GP-Pharm S.A. - Spain 1
Laboratorios del Dr. Esteve, S.A. - Spain 2
Lipopharma Therapeutics SL - Spain 1
Minoryx Therapeutics S.L. - Spain 1
Natac Pharma S.L. - Spain 1
NOSCIRA, S.A. - Spain 1
Oryzon Genomics SA - Spain 1
Pharma Mar SA Sociedad Unipersonal - Spain 8
Prodimed S.A. - Spain 1
ProRetina Therapeutics S.L. - Spain 1
ProRetina Therapeutics S.L.
- Spain 1
Sanifit Laboratoris, S.L. - Spain 1
TiGenix S.A.U. - Spain 3
Valentia BioPharma S.L - Spain 1
Vall d'Hebron Institute of Research - Spain 1
VCN Biosciences S.L. - Spain 1
Total general 40

19. 19
Orphan Drug Designations: Spanish sponsorships (from
April 2000 to September 2014)
Sponsor Active Substance Proposed Indication
Vall d'Hebron Institute of
Research - Spain
Vector based on an adeno-
associated virus serotype 2
backbone, pseudo-serotyped with
a type 8 capsid, which carries the
coding sequence of the human
TYMP gene under the control of
the human thyroxine binding
globulin promoter (Common)
Treatment of mitochondrial
neurogastrointestinal
encephalomyopathy
On 22 August 2014, orphan designation (EU/3/14/1326) was granted by the
European Commission to Vall d’Hebron Institute of Research, Spain.

20. 20
Orphan medicines authorized in EU

21. 21
Orphan medicines authorized in EU

22. 22
COMP/EMA: Orphan drug designation
achievements
¿?

23. Research and
Innovation
• 92 orphan medicines authorised
by the EC covering 98 therapeutic
conditions
• 1300 medicines under research
and development designated as
orphan medicines
• 1232+ designations given by the
EC covering ~ 521 conditions
Main gap: differences between ODD for
investigational and OD approved
©nyul/Fotolia.com

24. 24
Contenido de la presentación
1. Marco regulatorio europeo de medicamentos huérfanos
2. Incentivos, criterios de designación y procedimientos
reguladores
3. Estrategias de futuro
PROGRESSIVE EVIDENCE

25. 25
Hurdles on
development
orphan
medicines
Development
conventional
medicines

26. 26
First action: Increase Scientific Advice /
Protocol Assistance
• A tool that bring together all stakeholders involved to give the best
recommendations to sponsors in optimizing drug development to meet
the standards required for marketing authorization
• A meeting point to merge views from:
• Industry / Sponsor
• Academics / experts
• Patient associations
• Regulatory decision-makers: COMP/CHMP/CAT/PDCO
• HTA participation
• Possible (if wished): joint SA for USA (FDA) and EU (EMA)
• Aimed to solve the gap between designation and authorization 
Great importance to apply

27. 27
Impact of SA/PA in marketing authorisation
opinions
56.82%
75.00%
43.18%
25.00%
0.00%
10.00%
20.00%
30.00%
40.00%
50.00%
60.00%
70.00%
80.00%
Without SA With SA
Positive opinion
Negative opinion

28. 28
Impact of adherence to SA/PA in marketing
authorisation opinions
60%
50% 50% 50%
53%
86%
100%
77%
100%
90%
0%
20%
40%
60%
80%
100%
120%
Primary
endpoint
Choice of
comp.
Duration Statistics total
negative opinion
Positive opinion

29. 29
Second action: The way forward,
improving the translational pathway
• Biomarkers
• Animal models
• Delivery mechanisms
• Proof of principle
Gene identification
Pathophysiology
• Diagnostic
• Natural history
• Patient registries
• Trial sites
• Outcome measures
Clinical
investigation /
Trials • Regulatory
requirements
• Ethics
• HTA/ Health Economics
• Pricing / Follow-up
• Access policies
Therapy delivery

30. Research and
Innovation
www.irdirc.org
200 therapies
and
means to
diagnose most
rare disease by
2020
A joint initiative between DG Research (EU) and
National Institute Health (USA) started on 2009

31. eurordis.org
Therapies SC Recommendations
31
Guide policies and funding strategies
to reach the goal of 200 new therapies
by 2020 based on IRDiRC Policies and
Guidelines adopted in April 2013.
Sources: TSC members and its 4 WGs:
Orphan Drug-Development and Regulatory Processes
Biomarkers for Disease Progression and Therapy Response
Chemically-derived products including Repurposing
Biotechnology-derived products including Cell & Gene
Therapies
ECRD 2014, Berlin

32. eurordis.org
Strategy for
TSC Recommendations
32
 Prioritise collaborative clinical development of
designated orphan products & other rare disease
therapies that have received scientific guidance from
regulatory agencies, with emphasis on highest unmet
patient needs with the potential to be approved by 2020.
 To ensure the pipeline beyond 2020, prioritise also
products at the non-clinical stage with strong proof-of-
concept to support plausibility and with a commitment to
apply for orphan designation and to seek scientific
guidance from regulatory agencies
ECRD 2014, Berlin

33. eurordis.org
TSC Recommendations
for Funding Priorities
33
IRDiRC funders should consider funding of rare disease
clinical trials through two possible mechanisms:
International collaborative rare disease research and orphan
medicine development (“that takes best advantage of unique
expertise and availability of special resources”), irrespective of
geography or nationality of the applicants
International alignment of themes and coordination of the
process for calls for proposals
ECRD 2014, Berlin

34. Research and
Innovation
HORIZON 2020
• The EU’s 2014-20 programme
for research & innovation
(around € 80 billion)
• A core part of Europe 2020, Innovation
Union & European Research Area
• Three priorities: Excellent science,
Industrial leadership, Societal challenges

35. 35
The last reflexion
• Fostering overall orphan drug development should contribute to
increase the working knowledge of rare diseases and bring new
therapies to those patients affected living with a rare disease…
• So… the access policies intended to ensure that professionals can
prescribe the use of authorized orphan medicines in appropriate
expert centers are becoming crucial to improve quality of life of rare
disease patients.
Who do that?

36. Designation and authorization of orphan
medicines. EMA
Active participation of AEMPS
Health Ministry: Price and reimbursement
conditions
AEMPS: Compassionate use and clinical trials
authorization
Integral health planning for RD and funding of health
and pharmacological interventions

38. DEPARTAMENT DE SALUT
SERVEI CATALÀ DE SALUT
Consell Assessor Malalties
Minoritàries
CAMM, 2009
C.A. Tractaments
Farmacològics d’Alta
Complexitat
CATFAC, 2010
Evidència
Impacte pressupostari

39. 39
• Equity in medicines acces for treatment of rare diseases
• Medium and long-term sostenibility of catalan health system
• Improve health outcomes
• Do not hamper therapeutic innovation
Catalan policies regarding orphan drugs

40. Budgetary impact of authorized OD and number of
patients treated in the catalan health system

41. Budgetary impact by ATC classification groups (2011)
15%
3%
12%
3%
2%
61%
1% 3%
Percentatgede la despesa total en funció de
la categoria ATC (Any 2011)
A.- Sistema digestiu i
metabolisme
B.- Sang i òrgans
hematopoètics
C.- Sistema cardiovascular
G.- Sistema genitourinari i
hormones sexuals
H.- Preparacions sistèmiques
hormonals, excloent hormones
sexuals i insulines
L.- Antineoplàsics i agents
immunomoduladors

42. Rare diseases and orphan
drug development are a
great opportunity for
researchers and clinicians
to further contribute to
increase knowledge
generation in rare diseases
by enhancing translational
research.
Be ready for it!