Clinical evaluation of novel therapies in haemophilia
Download
1 / 23

Clinical Evaluation of Novel Therapies in Haemophilia - PowerPoint PPT Presentation


  • 124 Views
  • Uploaded on

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.

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Clinical Evaluation of Novel Therapies in Haemophilia' - semah


An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
Clinical evaluation of novel therapies in haemophilia

Clinical Evaluation of NovelTherapies 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


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 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


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 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!


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!


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 b
Orphan Drug Designation for Haemophilia B

Source: ema website


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



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 ?



ad