1. Per Nilsson, MD, PhD Medical Products Agency Sweden
Application for marketing authorisation of orphan drugs - the European experience -
Per Nilsson, MD, PhD
Medical Products Agency
Sweden

2. Authorisation of Orphan Drugs in Europe History (1)
Pre 1998 and ongoing
Marketing authorisation through national approval and mutual recognition
1998 Commission proposal for Community Procedure
Designation of orphan drug status
Incentives for development and authorisation
Market exclusivity

3. Authorisation of Orphan Drugs in Europe History (2)
1998 Commission proposal for Community Procedure
2000 OrphanDrugs Regulation 141/2000 (EC)
Designation criteria (COMP evaluation, EC decision)
Prevalence ≤5/10,000
Life-threatening or chronically disabling disease
No satisfactory method or ”significant benefit”
Incentives for development and authorisation
Fees, Protocol Assistance
Market exclusivity in indication 10 years
for ”similar” substance unless ”clinically superior”
Marketing authorisation (CHMP evaluation, EC decision)
Full access to Community MA procedure
”Normal” evaluation criteria (Q,S;E)

4. Authorisation of Orphan Drugs in Europe History (3)
1998 Commission proposal for Community Procedure
2000 OrphanDrugs Regulation 141/2000 (EC)
2001 First Community marketing authorisations of designated orphan drugs
Fabrazyme
Replagal

5. Authorisation of Orphan Drugs in Europe History (4)
1998 Commission proposal for Community Procedure
2000 OrphanDrugs Regulation 141/2000 (EC)
2001 First Community marketing authorisations
2005 Revised pharmaceutical legislation
Centralised Procedure compulsory for orphan drugs

6. National Competent Agencies Network
The Centralised European Procedure
EMEA: European Medicines Agency, CHMP: Committee for Medicinal Products for Human Use; COMP: Committee for Orphan Medicinal Products;
BPWG: Working Group on Blood Products; BWP: Biotech Working Party; EWP: Efficacy Working Party; PhVWP: Pharmacovigilance Working Party; QWP: Quality Working Party; SAWP: Scientific Advice Working Party
SWP: Safety Working Party
EU Commission
(DG3 Industry/Pharmaceuticals/Cosmetics)
Standing Committee
EMEA
CHMP’s working parties :
BPWG, BWP, EWP,
PhVWP, QWP,
SAWP, SWP
Ad hoc groups
External experts (SAG)
CHMP
COMP
National Competent Agencies Network
Scientific and Regulatory Expertise

7. Centralised Procedure Outcome
EU marketing authorisation
One set of product information (SPC, PL)
European Public Assessment report
National information from NCA / other bodies to prescribers / patients

8. Orphan Designation Applications to COMP
2000
2001
2002
2003
2004
Total
No. of applications submitted 72 83 80 87
402
Positive COMP Opinions 26 64 43 54 61
248
Commission Designations 14 49 55
225
Final Negative COMP Opinions 1 3 2 7
Withdrawals after Submission 25 24 35 15
119

9. Submission of Orphan MAAs to EMEA

10. Orphan CHMP Opinions over time

11. Approved Orphan MAAs (I) End 2004
Seventeen authorisations granted to date
Fabrazyme for Fabry disease
Replagal for Fabry disease
Glivec for chronic myeloid leukaemia
Tracleer for pulmonary arterial hypertension
Trisenox for acute promyelocytic leukaemia
Somavert for acromegaly
Zavesca for Gaucher disease
Carbaglu for hyperammonaemia
Aldurazyme for Mucopolysaccharidosis
Busilvex (iv) for haematopoietic progenitor cell transplantation
Ventavis for pulmonary arterial hypertension
Glivec imatinib, in the meanwhile first line with extension of indication to children
Tracleer-bosentan: Primary PAH and PAH secondary to scleroderma without significant interstitial pulmonary disease
Ventavis: only Primary PAH
Trisenox-Arsenic trioxide: for induction of remission and consolidation in adult patients with relapsed/refactory acute promyelocytic leukaemia (APL), characertised by the presence of the t(15;17) translocation and/or the presence of the Pro-Myelocytic Leukaemia/Retinoic-Acid Receptor-alpha (PML/RAR-alpha) gene. Previous treatment should have included a retinoid and chemotherapy.
Somavert is indicated for the treatment of patients with acromegaly who have had an inadequate response to surgery and/or radiation therapy and in whom an appropriate medical treatment with somatostatin analogues did not normalize IGF-I concentrations or was not tolerated
Zavesca-Miglustat: Zavesca may be used only in the treatment of patients for whom enzyme replacement therapy is unsuitable
Aldurazyme-Laronidase: Mucopolysaccharidosis I (MPS I; -L-iduronidase deficiency) to treat the non-neurological manifestations of the disease
Busilvex-Busulfan: Busilvex (iv) followed by cyclophosphamide (BuCy2) is indicated as conditioning treatment prior to conventional haematopoietic progenitor cell transplantation (HPCT) in adult patients when the combination is considered the best available option, the oral foprmulation is used since a number of years for this condition
Onsenal:for the reduction of the number of adenomatous intestinal polyps in familial adenomatous polyposis (FAP), as an adjunct to surgery and further endoscopic surveillance (The effect of Onsenal-induced reduction of polyp burden on the risk of intestinal cancer has not been demonstrated

12. Approved Orphan MAAs (II) End 2004
Seventeen authorisations granted to date
Onsenal for Familial Adenomatous Polyposis
Photobarr for Barrett’s oesophagus
Litak for hairy cell leukaemia
Lysodren for adrenal cortical carcinoma
Pedea for patent ductus arteriosus
Wilzin for Wilson’s disease
Xagrid for essential thrombocythaemia

13. Other outcomes of Orphan MAAs end 2004
Two negative opinions
Serostim for AIDS wasting
Yondelis for soft tissue sarcoma
Seven applications for MA withdrawn
for amyotrophic lateral sclerosis
for methanol poisoning
for advanced cutaneous T cell lymphoma
for erythema nodosum leprosum
for pulmonary arterial hypertension
for multiple myeloma
for Wegener’s granulomatosis
Eleven centralised applications in review process
Four applications filed through Mutual Recognition

14. Orphan CHMP opinions

15. Challenges Regulatory decision on (very) small databases
MA should be based on ”normal” requirements

16. Overview clinical studies in positive CHMP opinions

17. Overview clinical studies in positive opinions
Efficacy Patients (active)
Safety patients
Fabrazyme
58 (29) 73
Replagal
41 (21) 43
Trisenox 52
251
Tracleer
246 (166)
174
Zavesca 82 96
Somavert
157 (111)
167
Carbaglu 12 20
Busilvex
102
103
Aldurazyme
45 (22) 55
Wilzin
191 bibliographic
255
Orfadin
207 compassionate
>500
Litak 63
523
Fabrazyme: The primary efficacy endpoint for the main Phase III study was reduction of the glucosphingolipid GL‑3 (which is the substrate of a-galactosidae) accumulation from the capillary endothelium of the kidney at week 20 (p<0.001).
Replagal: 2 studies, 1) During the first 24 weeks (study TKT003) there was a progressive effect of agalsidase on pain resulting in a statistical trend (p=0.081) compared to placebo. In the extension phase (TKT006) placebo patients switched to active treatment and for this population a statistical significant effect could be demonstrated (p=0.0025). 2) Compared with placebo, treatment with agalsidase resulted in a reduction of cardiac GL-3 storage. (p=0.42).
Glivec CML: The effectiveness of Glivec is based on overall hematologic and cytogenetic response rates measured by conventional techniques, such as bone marrow cultures and assessing metaphases for Ph+ chromosome . There are no controlled trials demonstrating a clinical benefit or increased survival.
Glivec GIST: 40 PR and 40% stable disease
Trisenox: Overall, 45/52 (87%), clinical CR.Despite the lack of randomised controlled studies, the CR observed with ATO in the clinical trials presented shows that Trisenox has at least similar clinical efficacy to that reported in published series with ATRA+chemotherapy in patients with relapsed disease. However, the relatively short follow-up for the ATO trials does not guarantee that long-term remission is maintained in a high proportion of patients.
Tracleer: An improvement of exercise capacity (6 minute-walk test) from baseline was shown after 16 weeks increase from baseline was 36.4 meters [95% CI 24.9 meters, 47.8 meters]. A significant treatment effect as compared to placebo was shown; meter, some not conclusive evidence for dose-response
Zavesca, out of three studies with 82 patients, 28 one with 28 was considered as the main one at the end, from HIV trials for safety
Somavert: The proportion of subjects with normalized IGF-I concentrations was significantly greater for each of pegvisomant doses at each time point compared to placebo. No randomised clinical trial has been carried out versus an active treatment. Historical comparison to somatostatin analogues considered inconclusive.
Carbaglu Carbamoylglutamioc acid: 12 patients treated by 10 physicians in 5 different countries out of a total of 22 patients treated in the last 25 years
Aldurazyme: Two primary endpoints were selected for the pivotal study:% of predicted FVC , significant, and 6-minute walking distance, non significant trend, no clinical data on neurological manifestations of the condition.
Busilvex: Demonstration of pharmacokinetic comparability, the non comparative small trials of short duration did not allow conclusions on survival or disease free survival

18. Challenges and tools Regulatory decision on (very) small databases
Restricted authorisation
Approval under Exceptional Circumstances
Conditional Approval
EU Compassionate Use

20. Challenges and tools Regulatory decision on (very) small databases
Restricted authorisation
Approval under Exceptional Circumstances
Conditional Approval
EU Compassionate Use
Improving methods for data interpretation and study designs
Work within CHMP Efficacy Working Party
Implementation through Protocol Assistance

21. Challenges
Prospective learning from post-marketing experience

22. Challenges and tools
Prospective learning from post-marketing experience
Making Marketing Authorisation a (new) Starting Point
Constructive / Feasible Obligations
Aiming at maximal data generation on targeted issues
Interaction with Scientific Advice / Protocol Assistance
Some degree of across-products perspective

23. Tracleer (bosentan) Endothelin receptor antagonist for PAH
Pivotal study vs. PLA
Significant effect in primary endpoint: 6 min walking distance in patients with PAH stage III
Safety concern: High incidence of LFT elevation of unclear significance
SO Pharmacovigilance: TRAX PMS system
Centralised supply (per country)
Identification of prescribers
Information to identified prescribers
Solicited, selective AE reporting to Internet-based system

24. Tracleer (bosentan) 5th TRAX report March 2004

25. Challenges and tools
Prospective interaction during product development
Improved use of Protocol Assistance
New therapies/technologies
Small and medium-sized enterprises
Transparency and proactivity
Increased expert consultation
including patient representatives

26. Challenges and tools
Issues of ”signficant benefit”, ”similarity” and ”clinical superiority”
Significant benefit – COMP
Similarity/superiority – CHMP
EC draft guideline released for consultation

27. Orphan Drugs- the European experience from CHMP level
Orphan Drug Regulation is a working legal basis
Large influx of products to Community Register
Reasonable number of MAA with reasonable success rate
Worthwhile addition to patient care
Licensing Procedure functional - in evolution
Able to produce consistent and predictable decisions
Can improve on Protocol Assistance use and performance
May benefit from additional regulatory tools
conditional approval
Will gain from improved quality and focus of post-marketing obligations
importance of external expertise