Quality Assurance in Haemophilia A Therapy:

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Quality Assurance in Haemophilia A Therapy
A Pharmacovigilance Evaluation (PE) with
ReFacto in Germany - 3 Years of Clinical
Experience -
Data Monitoring Board Members H.-H. Brackmann,
Bonn L. Heinemann, Berlin W. Kreuz, Frankfurt
H. Lenk, Leipzig J. Oldenburg, Wuerzburg H.
Pollmann, Muenster W. Schramm, Munich T. F.
Schwarz, Wuerzburg R. Zimmermann, Heidelberg
N. Zavazava, Iowa City, USA
Dr. Hartmut Pollmann
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Introduction

• Pharmakovigilance
• In accordance with the Commitee for
• Medicinal Products (CPMP)
• Under routine conditions
• Individual therapy and dosage
• 67/6 AMG, 29/1 AMG Obligation to disclose
• (Bundesinstitut f. Arzneimittel und
  Medizinprodukte,
• BfArM)
• Non-intervention
• Since launch on April 13, 1999 of ReFacto

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Pharmacovigilance Evaluation What for?
PE
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Inclusion Criteria

• Inclusion of centers
• There are no other inclusion criteria than the
  agreement to
• participate actively in the evaluation. All
  specialized centers
• in Germany will be approached regarding
  participation in this evaluation.
• Inclusion of patients
• Patients suffering from hemophilia A verified by
  factor
• measurement
• Patients with inhibitor activity if physician
  determines
• potential benefit from drug

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Rationale

• Description of postulations of PE and statement
  that it is the suitable instrument
• Inclusion criteria (resp. exclusion criteria)
  of patients and
• selection of participating physicians
• Rationale of quantity, i.e. number of
  participating patients
• Rationale of type and quantity of documentation
• Precautions to guarantee quality assurance

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Design

• Multicenter, open-lable surveillance of patients
  treated
• with ReFacto in (specialized) health care
  centers under
• everyday life conditions determined by the
  treating physician
• (non-interventional character).

Dosage and Administration
Dosage, administraton and duration of therapy
will be determined by the physician to meet the
patients individual needs for treatment.
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Baseline and Follow-up Evaluation
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Patient Description I (11/2001)

• 136 patients with haemophilia A
• 27 centers included
• 91.2 patients FVIIIClt2
• 113 PTPs, 23 PUPs

Statistical Definition of Treatment Schemes
routine prophylaxis 67 patients on-demand
treatment 14 patients under evaluation 56
patients
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Patient description II (11/2001)
Age distribution corresponding to therapy scheme.
Data are numbers (N) of patients
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Results I (11/2001)

• Positive assessments of investigators and
  patients
• regarding usefulness.
• Data are percent values of number of
  physicians/patients

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Results II (11/2001)
Bleeding frequencies and dosage of F VIII of
prophylactic vs. on-demand treated patients.
Data are given as median values
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Safety and EfficacyInhibitor development in PUPs

• 2/13 PUPs developed an inhibitor (15.3)

For 8 PUPs we could calculate the number of
exposure days (EDs) until time of this
evaluation. The mean value for ED was 53, with 4
patients lt 20 EDs, 2 patients with 20-50 EDs
and 2 patients gt100 EDs.
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Genotyping

• Dr. Oldenburg -
• Genotyping of PE-patients
• Current Status
• gt 49 patients have been successfully genotyped
• distal Intron 22 inversion 19 patients
• proximal intron 22 inversion 4 patients
• missense mutation 8 patients
• small Deletion 6 patients
• large Deletion 2 patients
• splice site mutation 3 patients
• Stop 4 patients
• small insertion 3 patients
• gt 23 patients under further evaluation

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Summary and Conclusion

• 3 years of experience verify safety and
  efficacy of ReFacto in PUPs and PTPs
• No transmission of viral infections were
  detected.
• PE evaluates under routine therapeutic
  conditions efficacy, patients condition and
  safety. Therefore, PE is a useful tool for
  quality assurance in drug monitoring.
• In the on-demand group bleeding episodes (soft
  tissue joint) were about 4 times more frequent
  than in the prophylactic treated group of
  patients.

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Bluter

• Gefährdet ist ein allzu guter
• Und weicher Mensch er ist ein Bluter!
• Kaum, daß man ihn ein bißchen ritzt,
• Mit einem Scherz, der zu gespitzt,
• Mit einem Tadel, noch so mild
• Er ist verletzt, sein Herzblut quillt.
• Und bringt man es nicht zum Gerinnen,
• Verblutet sich der Mensch - nach innen.

Zitat aus Von Mensch zu Mensch von Eugen Roth