Transcript Biogenerics - European Health Forum Gastein

Biosimilar medicines and patient safety:
making an informed decision
European Health Forum Gastein – EHFG 2005
Kurt Pfister
PFC Pharma Focus AG
Volketswil/Zürich - Switzerland
PFC Pharma Focus Ltd
06.10.2005
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Agenda
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
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The risks – for originator as well as “generic” companies
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Biological Medicinal Product – off-patent and now?
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Impact of the different nature of the medicinal products
on the marketing authorization process
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Cautious approach of the regulatory bodies
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Summary Remarks
PFC Pharma Focus Ltd
06.10.2005
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
The synthetic medicinal product
Production
PFC Pharma Focus Ltd
06.10.2005
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
The synthetic Medicinal Product
Product
Aspirin
PFC Pharma Focus Ltd
Penicillin
•
simple
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small
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easily characterized
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clean
06.10.2005
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
The medicinal product from a biotechnology-derived protein
Production
Gene transfer
Source of production site
Production site
PFC Pharma Focus Ltd
06.10.2005
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
Prof. Florian Wurm, 10. Reg. Forum 2005
PFC Pharma Focus Ltd
06.10.2005
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
Biotech-Wirkstoffe werden eher gebraut als chemisch
konstruiert. In riesigen Fermentern schwimmen Kulturen
genetisch veränderter Bakterien in Nährlösung. Aus dieser
Biosuppe werden die Wirkstoffe extrahiert und gereinigt.
Sie bestehen aus Proteinen, die auch natürlich vorkommen
- oder ähneln diesen zumindest.
PFC Pharma Focus Ltd
06.10.2005
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
The medicinal product from a biotechnology-derived protein
Product
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Production site complex
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Product very large
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Heterogeneity in structure
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Difficult to characterize
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Difficult to clean
Factor VIIII
Fred Hutchinson Cancer Research Center
PFC Pharma Focus Ltd
06.10.2005
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
Difference in complexity
Molecular
Weight (Dalton)
Product
Number of
Amino Acids
Chemically-Based
Biologic
Propranolol
259
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Aspirin
180
-
4,500
32
22,000
191
ca. 30,000
165
ca. 264,000
2332
Calcitonin
Hu Growth Hormone
Erythropoietin
Factor VIII
PFC Pharma Focus Ltd
06.10.2005
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
Difference in complexity
PFC Pharma Focus Ltd
06.10.2005
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
Difference in post-translational modification
Ram Sasisekharan, MIT, FDA Public Workshop, September 14 & 15, 2004
PFC Pharma Focus Ltd
06.10.2005
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
Change of the production site and system expl. Erythropoetin
Schellekens, H., Biosimilar Epoetins: How Similar Are
They? Eur. J. of Hosp. Scien., Mar 04, 43-47
PFC Pharma Focus Ltd
06.10.2005
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
Ob bei zwei biotechnischen Prozessen wirklich
Gleichwertiges herauskommt, haben sogar deren Erfinder
nicht immer im Griff.
PFC Pharma Focus Ltd
06.10.2005
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The risk –
for originator as well as “generic” companies
PFC Pharma Focus Ltd
06.10.2005
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The risk – difference in efficacy
Impact of small structural differences on bioavailability
Site of Carbohydrate Linkage – Opioid Glycopeptide (Elmagbari et al.)
JPET 311:290-297, 2004
PFC Pharma Focus Ltd
06.10.2005
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The risk – difference in efficacy
Impact of small structural differences on tissue distribution
Biodistribution of Radiolabeled Glycoforms in Mice*
Tissue
Form 1
Form 2
Form 3
Form 4
Blood
100%
108%
103%
217%
Liver
100%
51%
13%
4%
Lungs
100%
22%
56%
289%
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Bone Marrow
* Neoglycopeptides (derived from fibrinogen, thyroglobulin)
25 minutes post-dose, cpm  108 gm tissue
Gupta and Surolia. 1994
Glycoconjugate Journal
PFC Pharma Focus Ltd
06.10.2005
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The risk – difference in safety
The event, which changed perception
PFC Pharma Focus Ltd
06.10.2005
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The risk – difference in safety
... the observation
Bennett C.NJM, 2004; 351, 1403
PFC Pharma Focus Ltd
06.10.2005
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The risk – difference in safety
... and the analysis
Bennett C.NJM, 2004; 351, 1403
PFC Pharma Focus Ltd
06.10.2005
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Synthetic versus biotechnology-derived Medicinal
Products – the difference
„The process makes the product“
Any change in the production may
change the product
Any change in the product may
change the efficacy and safety
PFC Pharma Focus Ltd
06.10.2005
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Biological Medicinal Product – off-patent and now?
Brand
Active Substances
Marketer
Approval
1999: $ Mio
Epogen
Epoetin alfa
Amgen
1989
1760.0
Procrit
Epoetin alfa
Ortho
1990
1505.0
Neupogen
Filgrastim
Amgen
1991
1260.0
Humulin
human Insulin
Eli Lilly
1992
1088.0
Intron A
Interferon alfa-2b
Schering
1986
650.0
Engerix-B
Hepatitis B vaccine,
Biogen
1989
540.0
Ceredase
Alglucerase
Schering
1991
500.0
Cerezyme
Imiglucerase
Genzyme
1991
479.0
Betaseron
Interferon beta-1b
Eli Lilly
1993
413.0
Kogenate
Antihemophilic factor
Centocor
1993
403.4
Quelle: Arthur D. Little, USA 1999
PFC Pharma Focus Ltd
06.10.2005
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Biological Medicinal Product – off-patent and now?
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Sales of biopharmaceutical markt coming off-patent
appox. 12 billion USD
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USA
EU
Japan
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Assumption Biosimilar-Penetration 10 bis 15%:
2 billion USD
PFC Pharma Focus Ltd
45%
30%
20%
06.10.2005
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Biological Medicinal Product – off-patent and now?
PFC Pharma Focus Ltd
06.10.2005
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Biological Medicinal Product – off-patent and now?
Why are the first “biosimilars“ not yet on the market?
PFC Pharma Focus Ltd
06.10.2005
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Impact of the different nature of the medicinal
products on the marketing authorization process
Approval process synthetic medicinal product
Efficacy
Pharmaceutical
Quality
Bioavailablity
Safety
PFC Pharma Focus Ltd
06.10.2005
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Impact of the different nature of the medicinal
products on the marketing authorization
Approval process synthetic „generic“
Pharmazeutische
Qualität
Sicherheit
Bioäquivalenz
Pharmazeutische
Qualität
Wirksamkeit
Innovator product
PFC Pharma Focus Ltd
Substitution
06.10.2005
Generic product
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Impact of the different nature of the medicinal
products on the marketing authorization
Approval process „biosimilar“
Pharmazeutische
Qualität
Pharmazeutische
Qualität
Sicherheit
Sicherheit
Bioäquivalenz
Wirksamkeit
Wirksamkeit
Innovator product
PFC Pharma Focus Ltd
Substitution
06.10.2005
Biosimilar
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Cautious approach of the regulatory bodies
Biogenerics
Biosimilars
Follow on Protein (FOP)
Follow on Biologics (FOB)
PFC Pharma Focus Ltd
06.10.2005
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Cautious approach of the regulatory bodies
No specific guidelines on biosimilars
„FDA Guidance concerning demonstration of comparability of
human biological products, including therapeutic biologically
derived products“ (April 1996)
PFC Pharma Focus Ltd
06.10.2005
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Cautious approach of the regulatory bodies
Revision of Directive 2001/83
(Entering into Force Nov' 2005)
Overarching
Quality
Guideline on Similar Biological Medicinal Products
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Guideline on Similar Biological Medicinal Products
Containing Biotechnology-Derived Proteins as Active
Substance: Quality Issues
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Nonclinical
& Clinical
Guideline on Similar Biological Medicinal Products
Containing Biotechnology-Derived Proteins as Active
Substance: Nonclinical & Clinical Issues [comments due Oct ‘05]
Annexes
Recombinant
Human
Erythropoietin
PFC Pharma Focus Ltd
Recombinant
Human
G-CSF
Recombinant
Human
Insulin
06.10.2005
Recombinant
Human Growth
Hormone
General:
Applies to all
Biosimilars
Specific:
Product data
requirements
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Cautious approach of the regulatory bodies
3 Biosimilars
Reaction expected 3. / 4.Q 2005
Human Growth Hormone
INF-alpha
Produkt ???
PFC Pharma Focus Ltd
06.10.2005
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In Summary
original ***** similar?
Complexity of production of biologicals
Complexity of structure of biologicals
Not identical, but similar (how much?)
Risk
Substitution ?
PFC Pharma Focus Ltd
06.10.2005
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