Clinical Evaluation of Novel Therapies in Haemophilia

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Clinical Evaluation of Novel Therapies in Haemophilia. Dr. Anneliese Hilger Paul-Ehrlich-Institut. EHC Roundtable of Stakeholders Brussels, 7 December 2011 . Agenda Regulatory Background Drafting Process Clinical Trial Concept Efficacy+Safety Guideline Summary Open issues.
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Clinical Evaluation of NovelTherapies in HaemophiliaDr. Anneliese HilgerPaul-Ehrlich-InstitutEHC Roundtable of StakeholdersBrussels, 7 December 2011 Agenda
  • Regulatory Background
  • Drafting Process
  • Clinical Trial Concept
  • Efficacy+Safety
  • Guideline
  • Summary
  • Open issues
  • 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
  • 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
  • Drafting processNotes for Guidance on the Clinical Investigation andcore SPCs of recombinant and plasma-derived FVIIIand 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
  • 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
  • Clinical Trial Concept FVIIIPre-authorisationPost-authorisation50PK in 12 PTP> 12yEfficacy+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 to100 ED, „new“ PTP for 100 ED; at least 60 PTP <12y should be Included)Pre-defined sampling time points20 PTP > 12y, 50 EDPK in12 PTP6-12y25 Children(E+S)6-12y (PTP) for 50 ED50PK in120-6y25 Children(E+S)0-6y (>50ED) for 50 ED20pts <12y, 50ED50 PUP (E+S)for 50 ED100 PUP;100EDpost-approvalSmPC for novel products: restricted indication until data from 50 PUP (E+S) are available!Clinical Trial Concept FIXPre-authorisationPost-authorisation20PK in 12 PTP> 12yEfficacy+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 to100 ED, „new“ PTP for 100 ED; Pre-defined sampling time points10 PTP > 12y, 50 EDPK in10 PTP6-12y10 Children(E+S)6-12y (PTP) for 50 ED20PK in100-6y10 Children(E+S)0-6y (>50ED) for 50 ED10pts <12y, 50ED20 PUP (E+S)for 50 ED20-40 PUP;100EDpost-approvalSmPC for novel products: restricted indication until data from 50 PUP (E+S) are available!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
  • 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)
  • 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
  • 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 ?
  • Orphan Drug Designation for Haemophilia ASource: ema websiteOrphan Drug Designation for Haemophilia BSource: ema websiteOrphan 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
  • Similar Medicinal Product?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 ?
  • Paul Ehrlich
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