Prof. Dr. János Borvendég
CHMP member
Hungary

The market is driven by two factors:
 by unmet clinical needs (diseases unmanageable with conventional therapeutics)
 by a premium price

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10 % - 15 % of the world pharmaceutical market
 growth between 2004-2010:
3,4 % year for total market
11 % year for biopharmaceuticals
 biosimilar market in EU + US 16,4 billion $ by 2011

imiglucerase human insulin somatropin interferon alfa interferon beta erythropoietin filgrastim tPA
IL-2 sterptokinase

global sales
Erythropoietin 13 billion
1,9 billion Human growth hormone
Recombinant human insulin
Interferon alfa
8,0 billion
2,3 billion
3,7 billion Interferon beta
G-CSF 5,6 billion
* EU markets only
** US + major EU markets growth
7 %
2 %
6 %
15 % proportion in
US market
69 %
33 % predicted sales
2010
* 701 million
** 442 million
** 138 million
35 %
55 %
63 %
** 188 million
* 131 million
** 605 million

USA:
„Promoting Innovation and Access to Life-Saving
Medicine Act” HR. 1427
(11.03. 2009)
Mr. Waxman’s bill
„Pathways for Biosimilars Act” (draft)
Mrs. Eshoo bill (competing approach)

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 definition (biological, reference product) regulations of Biosimilars and Interchangeable biological products submission of abbreviated biological product application approval of biosimilar or Interchangeable biological products determinations on interchangeability market exclusivity for the original and biosimilar/interchangeable products
-*standard requirements for biosimilarity and for interchangeability have to be established by the FDA
(within 2 years of passage of the bill).

Recent regulatory issues in biosimilarity assessment and acceptance by the Regulatory Agencies
EU/EMEA
Several guidelines on
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Comparability exercises (non-clinical/clinical)
EMEA/CHMP 49348/2005
EMA/CHMP 42832/2005
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PK of therapeutic proteins
EMEA/CHMP 89249/2004
Immunogenicity assessment
EMEA/CHMP/BWP/24511/2005
Quality issues
EMEA/CHMP/BWP/3204
-EMEA/CHMP/BWP/49348/2005
Validation of bioanalytical methode
EMEA/CHMP/EWP/531305/2008 (concept paper)
Development, production, characterisation and specification for mAB and related products
EMEA/CHMP/BWP/157653/2007

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BP have different levels of complexity
The regulatory requirements are guided (on case by case basis) by the
- extent of the physicochemical/biological characterisation of the product,
- nature of possible changes in the quality/structure of the biological product due to the changes in the manufacturing process (and their expected outcomes)
- clinical/regulatory experiences with the particular class of the product in question
The „traditional” bioequivalence (PK/PD) studies can not be applied with the same relevance

Biosimilar, or similar biological medicinal product is „a new biological medicinal product, similar to licensed reference medicinal product” in: - quality
- efficacy
- safety
Biological medicinal products: contain biotechnology derived products as active substance
Biosimilar and reference biological medicines are similar but not identical

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Complex manufacturing process
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High molecular weight
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Complex 3-D structure
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Difficult to characterize
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Stability problems
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Immunogenicity

Factors which may change the structure of the proteins during the manufacturing process (even under strictly controlled condition).
Chemically: oxidation, deamidation, disulfide shuffling racemisation
Physically: unfolding misfolding aggregation precipitation fragmentation

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„full” Quality dossier is required
„State of Art” analytical methods
(physicochemical plus bioanalytical)
Additional elements
- comparability exercise
- focusing on possible differences in: manufacturing process minor structural diff.
impurities

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Comparative studies (similarity and differences at several doses level) in vitro: receptor binding in vivo: cell based assays
PK/PD
Toxicity: spec. tox.
rutin tox.?

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Requirements depend on
- type/properties of the biological product
- extent of the physicochemical/biological characterisation
- non-clinical analysis
- therapeutic indication
- clinical experiences of the reference product
Stepwise procedure:
- PK
- PD
- Therapeutic equivalence studies

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The requirements for PK studies are the same as for conventional product
(single dose/steady state studies)
Specific problems of bio-analysis
- validation of the analytical assay
(specificity, accuracy, precision, limit of detection)
- methodological problems drug assay (interference with endogen substances) antibody assay (presence of the active substance in the plasma)
Specific problems in PK clinical studies
- great variability (inter/intra subject)
- immunogenicity (antibody formation)
 change in PK parameters

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Availability of PD markers/surrogate biomarkers
Sensitivity to changes in activity?
Do they signal clinical endpoints?
Is there quantitative relationship between the surrogate and clinical endpoint?
Is there correlation between the PK an PD values?
Are they validated?

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General recommendations
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Are these clinical trials really needed?
It depends on: mechanism of action of the biological product
(disease specific?) indication (target organ)
PK properties availability of surrogate markers safety profile and immonogenicity of the product sensitivity of the clinical study clinical experiences with the reference product

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Individualized regulatory requirements for clinical comparative studies
Recombinant human insulin (rh Insulin)
PK: single dose, cross-over (in patients with type II diabetes)
AUC, Cmax, tmax, t/2
PD: double blind, cross-over (euglycaemic clamp)
Efficacy: waived if the biosimilarity is justified by
PK/PD data
Safety: 6 months (Pre-approval) study
12 months (Post-marketing) study commitment
PhV.P: - allergic reactions
- compare the daily dose of previous and of the new insulin, needed by the patients

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Individualized regulatory requirements for clinical comparative studies
(cont.)
Human Somatropin (rSTH)
PK: single dose, cross-over comparative s.c. in healthy volunteers (AUC, Cmax, tmax, t/2)
PD: biomarkers IGF-1
IGF BP-3
Efficacy:
- comparative, double blind, parallel groups in hypophyser dwarfs
- endpoints: growth in cm/year, SD score
- duration: 6-12 months
Safety: immunotoxicity (12 months)
IGF-1, IGF BP-3, insulin, plasma glucose
PhV.P: - diabetogen effect
- incidency of malignancy
- anti rh GH antibodies

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Individualized regulatory requirements for clinical comparative studies
(cont.) rG-CSF
PK: single dose, cross-over comparative
(s.c./i.v.)
(AUC, Cmax, tmax, t/2)
PD: absolute neutrophil count. (CD34)
Efficacy: (indications)
- mitigation of neutropenia
(at chemo th./myeloablative th)
- mobilisation of progenitor cells
- congenit./idiopathic neutropenia
Safety: - 6 months comparative trial
- immunogenicity
PhV.P/Risk Management Program

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Individualized regulatory requirements for clinical comparative studies
(cont.)
Interferon alfa
PK: single dose, cross-over s.c./i.v.
healthy volunteers
PD:  -2 microglobulin
- neopterin
- se 2’, 5’ –oligoadenylate synthetase activity
Efficacy:
- randomised, parallel group, comparative
- treatment naive patients with HCV  48 weeks
Endpoints:
- undetectable levels of HCV RNA (by quantitative
PCR)
- co-primary endpoint: 2-10 log decrease in viral load
Safety: - flu-like illness, alopecia, myalgia, leucopenia, anaemia, thrombocytopenia = Ref. Prep.
- immunogenicity/neutralising capacity
Extrapolation: „if the mechanism of actions known to be the same condition”

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Individualized regulatory requirements for clinical comparative studies
(cont.)
Low Molecular Weight-Heparins
PK: not applicable
PD: single dose, randomized, cross-over healthy volunteers surrogate markers: anti F Xa anti F 11a activity
TFPI
Efficacy:
- randomised, double blind, parallel group th. equivalence study
- prevention of venous/arterial thrombolism treatment /VTE, DVT, PE)
- patients with major orthopedic surgery ultra sonography renography death
Safety: - major bleeding
- heparin induced thrombocytopenia
PhV.P/Risk Management Program

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(cont.)
Recombinant Erythropoietins
PK: single dose, cross-over, comparative (s.c./i.v.)
PD: comparative, multiple dose (4 weeks) dose ascending endpoint: change in Hgb
Efficacy:
- comparative, randomized, parallel groups, double blind
▫ correction phase (s.c.)
▫ maintenance phase (i.v.)
- target population (anaemia due to chronic renal faliure)
- 6 month
- endpoints: Hgb level – in correction/maintenance phase the reacting patients in % epoetin dosage transfusion requirements
Safety: immunotoxicity (12 months, comparative)
Ph.V.P. + Risk Management Program
Extension to other indication: allowed

Teva Pharmaceuticals – Lonza (Basel)
Biopartners (Barr, Switzerland) – Bioton rGH, Alpheon (interferon alfa)
Sandoz (generic arm of Novartis (Basel)
Merck Co. Merck Bio Ventures
Omnitrope (rGH)
Binocrit (Epoetin alfa Hexal) filgrastim
Insmed (Richmond VA) rG-CSF pegylated rG-CSF

Hospira (Lake Forest)
Phage (Biotechnology, San-Diego)
Gene Medix (Offaly, Ireland)
Dragon Pharmaceutical (Vancouver)
Shanta Biotech (New Delhi)
Bharat Biotech (Hyderabad, India)

Hurdles in the faster growth of biosimilar market
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Biosimilars are specific products
Regulations for marketing approval are much stricter than those for conventional generics
The required capital investment and cost of manufacturing are much higher for biosimilars and the probability of successful lauch is lower than those for chemical-based generics

Hurdles in the faster growth of biosimilar market
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(cont.)
Post-approval safety monitoring is compulsory
Manufacturers of innovator/branded products are likely use sophisticated defensive tactics
(improved delivery devices, improving the PK properties of the original products etc.)
Physicians are reluctant to switch to biosimilar products
Relatively small price differentce (20-25 % discount optimum) reduces the incentive to switch.

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 the majority of BP-s is of very important medicine (including th. for cancers, genetic diseases) the price of the innovator BP-s is extremely high to curb the healthcare spending and to promote the access to life-saving medicines are in the interest of the whole society

Key factors:
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Capital investment
- financial strength
- combination of generic and branded business
- licensing, collaborations, and mergers
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Development expertise in:
- manufacturing proteins
- sophisticate analytical methods
- clinical studies (comparative PK/PD/Th studies)
Marketing expertise in sales, promotion, safety monitoring
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Rational and flexible regulation of marketing authorisation. Simplified guidelines.
Suitable price policy / price competition
The financial policy / capability of the Social Security system

I am optimistic….
and you?