Clinical Evaluation of Novel Therapies in Haemophilia

1. Clinical Evaluation of NovelTherapies in Haemophilia Dr. Anneliese Hilger Paul-Ehrlich-Institut EHC Roundtable of Stakeholders Brussels, 7 December 2011

2. Agenda • Regulatory Background • Drafting Process • Clinical Trial Concept • Efficacy+Safety • Guideline • Summary • Open issues

3. EU- Clinical Guidance • Note for Guidance - on the Clinical Investigation of Human Plasma Derived Factor VIII and IX Products (CPMP/BPWG/198/95) 1996, rev.1 2001- on the Clinical Investigation of Recombinant Factor VIII and IX Products (CPMP/BPWG/1561/99) 2001 • Core SPC- for Human Plasma Derived and Recombinant Coagulation Factor VIII Products (CPMP/BPWG/1619/99) 2000- for Human Plasma Derived and Recombinant Coagulation Factor IX Products (CPMP/BPWG/1625/99) 2000

4. Regulatory Background • New European legal requirements (e.g. Paediatric Regulation, RMP) • Class review on inhibitor development (rFVIII products) • Concept on Revision of NfG/core SPC initiated in 2004/2005: - pharmacokinetic aspects - clinical studies in children - ITI - Risk management plan - coreSPC update (e.g. transmissible diseases) • EMA workshop on inhibitors 2006

5. Drafting process Notes for Guidance on the Clinical Investigation and core SPCs of recombinant and plasma-derived FVIII and FIX: • first public consultation 2007 • Deadline comments 01/2008 • Stakeholder meeting 02/2008 • second public consultation 06/2009 • Deadline for comments 10/2009 • CHMP adoption in July 2011

6. General aspects: • pre- and post authorisation clinical trials for - new marketing authorisations- authorised products where a significant change should be made • Patient population: Previously treated Patients (PTP >150EDs) severity: <1% FVIII; <2% FIX;immunocompetent • Stepwise approach:start with pk in adults/adolescents >12y, continue withefficacy and safety for 50 Exposure days, when data areavailable start with pk in children <12y; start with PUP studywhen data from children study is available

7. Clinical Trial Concept FVIII Pre-authorisation Post-authorisation 50 PK in 12 PTP > 12y Efficacy+Safety (E+S) 50 PTP > 12y for 50 ED (12+38 patients) PMI:200 PTP for 100 ED (Patients from pre- Authorisation Studies can be followed up to 100 ED, „new“ PTP for 100 ED; at least 60 PTP <12y should be Included) Pre-defined sampling time points 20 PTP > 12y, 50 ED PK in 12 PTP 6-12y 25 Children(E+S) 6-12y (PTP) for 50 ED 50 PK in 12 0-6y 25 Children(E+S) 0-6y (>50ED) for 50 ED 20pts <12y, 50ED 50 PUP (E+S) for 50 ED 100 PUP;100EDpost-approval SmPC for novel products: restricted indication until data from 50 PUP (E+S) are available!

8. Clinical Trial Concept FIX Pre-authorisation Post-authorisation 20 PK in 12 PTP > 12y Efficacy+Safety (E+S) 20 PTP > 12y for 50 ED (12+8 patients) PMI:50 PTP for 100 ED (Patients from pre- Authorisation Studies can be followed up to 100 ED, „new“ PTP for 100 ED; Pre-defined sampling time points 10 PTP > 12y, 50 ED PK in 10 PTP 6-12y 10 Children(E+S) 6-12y (PTP) for 50 ED 20 PK in 10 0-6y 10 Children(E+S) 0-6y (>50ED) for 50 ED 10pts <12y, 50ED 20 PUP (E+S) for 50 ED 20-40 PUP;100EDpost-approval SmPC for novel products: restricted indication until data from 50 PUP (E+S) are available!

9. Efficacy • clinical response will be assessed by patient and physician(none, moderate, good, excellent) • Surgery5 patients with at least 10 surgeries (including major surgeries) =efficacy of haemostasis, blood loss, transfusion requirements + consumption (number of infusions and IU/kg per month and per year, as well as IU/kg per event (prophylaxis, on-demand, and surgery). • Continuous infusion12 PTP (<1%) undergoing elective major surgeriesinitial infusion rate based on clearance calculation

10. Safety • PTPs are most suitable to study product-related immunogenicity • Modified Nijmegen method of Bethesda assay performed in a central laboratory • Inhibitor definitions: low titer >0,6 BU high titer > 5 BU • Inhibitor monitoring following a predefined schedule (baseline,ED 10-15; ED 50-75; ED 100)

14. Key points • Guidelines + coreSPC • pd + rec FVIII • pd + rec FIX • Clinical concept comprising pre- and post authorisation trials • Staggered approach • Children to be investigated pre-authorisation • PK in adults, adolescents and children to be performed • PUP studies required for novel products (indication restricted) • Post marketing trials: predefined sampling points • ITI no longer within the scope of the guidelines • General principles should apply for all new Factor VIII and IX products including novel products • Guidelines: www.ema.europa.eu

15. 0pen issues…. • Plasma-derived vs. recombinant products • Full-length vs. B-domain-deleted • Treatment of inhibitor patients (Inhibitor eradication) • Inhibitor prevention (e.g. early prophylaxis) • Modified Proteins = which might be the best ?

16. Orphan Drug Designation for Haemophilia A Source: ema website

17. Orphan Drug Designation for Haemophilia B Source: ema website

18. Orphan drug designation • Orphan disease (HA approx. 0,6/10.000; HB approx. 0,1/10.000) • significant benefit for patients Market exclusivity • after granting of marketing authorisation • for 10 years • “similar” products will be not accepted

20. Similar Medicinal Product?

22. Concerns • first product getting MA must not be the optimal modification • Prolongation of T1/2 might be different • Immunogenicity profile might be different and might be detectable only after MA • Product developments without avail • Intention of European Legislative ?

23. Paul Ehrlich