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 Novel Therapies in Haemophilia

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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


Clinical evaluation of novel therapies in haemophilia

Agenda

  • Regulatory Background

  • Drafting Process

  • Clinical Trial Concept

  • Efficacy+Safety

  • Guideline

  • Summary

  • Open issues


Clinical evaluation of novel therapies in haemophilia

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


Clinical evaluation of novel therapies in haemophilia

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


Clinical evaluation of novel therapies in haemophilia

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


Clinical evaluation of novel therapies in haemophilia

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 evaluation of novel therapies in haemophilia

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 evaluation of novel therapies in haemophilia

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!


Clinical evaluation of novel therapies in haemophilia

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


Clinical evaluation of novel therapies in haemophilia

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 BUhigh titer > 5 BU

  • Inhibitor monitoring following a predefined schedule (baseline,ED 10-15; ED 50-75; ED 100)


Clinical evaluation of novel therapies in haemophilia

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


Clinical evaluation of novel therapies in haemophilia

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 a

Orphan Drug Designation for Haemophilia A

Source: ema website


Orphan drug designation for haemophilia b

Orphan Drug Designation for Haemophilia B

Source: ema website


Clinical evaluation of novel therapies in haemophilia

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


Similar medicinal product

Similar Medicinal Product?


Clinical evaluation of novel therapies in haemophilia

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 ?


Clinical evaluation of novel therapies in haemophilia

Paul Ehrlich


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