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DEVELOPMENT OF A
BIOSIMILAR IN THE E.U
Master 2 Réglementation du Médicament
dans l’Union Européenne
2011-2012
Thierry AHADJI, Pablo APIOU, Matthieu BOULENGER,
Caroline HABAUZIT, Marie VASSELIN
Introduction
Global sales of biological medicines have
grown rapidly during the past 30 years

With the patents expiry this market
appeared as a significant target for generic
companies

However, if the economic issues are
attractive the barriers to entry the market
are important

« Biosimilars offer new opportunities both for the
growth of our generic industry and for the control of our
national health expenditures »
Günter Verheugen (April 2006)
2
Contents
 1st part: Biosimilars outlines
 2nd part: Should a generic company
invest on biosimilars ?
 3rd part: Developing a hCG Biosimilar
3
1st part:
BIOSIMILARS
OUTLINES
4
Legal environment
Directive 2004/27/EC - Article 10:
2.(b) « generic medicinal product »
 same qualitative and quantitative
composition in active substances and
the same pharmaceutical form as the
reference medicinal product, and
whose bioequivalence with the
reference medicinal product has been
demonstrated by appropriate
bioavailability studies.
4. « biosimilars »
 where a biological medicinal product
which is similar to a reference biological
product does not meet the conditions in
the definition of generic medicinal
products, owing to, in particular,
differences relating to raw materials or
differences in manufacturing processes
of the biological medicinal product and
the reference biological medicinal
product, the results of appropriate preclinical tests or clinical trials relating to
these conditions must be provided.
5
Variability
“Key word” for Biologics products
•
Variability Linked to the molecule. Ex : Glycosylation profile
•
Variability Linked to impurities
6
Biosimilars are not biological generics!
The references can not be compared
Properties
Biotech drugs
Chemical drugs
Size
Large
Small
Structure
Complex
Simple
Stability
Unstable
Stable
Modification
Many
options
Manufacturing
Unique line of living cells. Predictable chemical process.
Impossible to make
Identical copy can be made.
identical copy
Characterization
Impossible to characterize
fully due to a mixture of
related molecules
Well-defined
Easy to fully characterize
7
Biosimilars are not biological generics!
Biosimilars are
similar…
… but not identical
8
Biosimilars are not biological generics!
Chemical product
Biological product
Due to the complexity and
variability of a biological, the
quality profile (and hence the
clinical profile) is determined
by the manufacturing process.
“The process makes the product”
Generic
Biosimilar:
Many possible
isoforms
9
Source : Afssaps « Des médicaments issus des biotechnologies aux biosimilaires : Etat des lieux »
«The process makes the product»
Ex: Variability induced in manufacturing changes for a commercial Mab
Even originators are « manufacturing biosimilars » of their original
products
Worldwide experience with Biosimilars development (Marc Mc Camish
and Gillian Woollett) – Landes Bioscience
10
Risks linked to the Quality profile changes
• Viral safety: need evidence of lack of adventitious agents in the MCB
(for recombinant proteins)
• Variability and the potential changes in quality profile
(detected or not) lead to the main problem for biosimilars
(and biologicals) :
IMMUNOGENICITY
Immunogenicity may have serious clinical consequences (in case
of neutralizing antibodies)

Safety

Efficacy (inhibition – up to complete loss – of the
therapeutic effect)
11
Immunogenicity
Nature Reviews – Drug discovery
12
Immunogenicity

Example of immunogenicity related to quality:
IFN alpha-2a


(a) Lyoph.+ HSA Room temp.
(b) Lyoph. + HSA Refrig.
(c) Liquid + HSA, Refrig.
(d) Liquid, HSA free, Refrig.
(e) Lyoph. HSA free, Refrig
It is not yet possible to fully predict the induction of antibodies
The relative immunogenicity of therapeutic proteins can only be
evaluated in clinical studies
13
Key issues
All these possible differences between a biosimilar and its
reference lead to 2 main questions:


How can the level of similarity be well established ?
How can the risks associated be defined ?
Debate on
substitutability
14
nd
2
part:
SHOULD A GENERIC
COMPANY INVEST ON
BIOSIMILARS?
15
Current market
• Limited market experience (Somatropine : 2006)
• Highest number of approvals : Europe  14 approvals (but for only 3 Active substances)
Somatropin
2006
EPO
Filgrastim
2010 16
Opportunities: Biologics Market expansion
 Almost 100 Mds $
 80% of hospital prescriptions
 12% of pharmaceutical market
 Several blockbusters
17
Opportunities: Biosimilars
Market expansion
Fierce competition from
large generics
Low price and faster market
penetration is expected
Biosimilars are
experiencing high demand
EPO
G-CSF
HGH
Existing Biosimilars
Emerging Biosimilars
Insulins
The high prevalence of
diabetes is leading to
the increased demand
Biosimilars
Market
IFN
Biosimilars are under
development
2009
2015
Mabs
Most awaited segment with
immense opportunity.
Significant target for
biosimilars developpers
Mabs
Market
size
36,4 Mds $
60 Mds $
18
Opportunities: Patents expiry
From well-established biosimilar proteins…
… to complexe large proteins biosimilars:
Mabs
19
However…


The actual european market of biosimilars is still limited ( < 20% of total
sales where they are present)
The market entry of biosimilars can't be compared to the market entry of
generics
Example of the French market:
Note that in Germany the
market entry of biosimilars is
important, for instance, in 2009
EPO biosimilars represented
29% of the global EPO market
20
Substitutability issues
Substitutability : “pharmacist 's ability to dispense a biosimilar rather than
the reference drug”
Overall GuideLine: « In order to support
PharmacoVigilance monitoring, the
specific medicinal product given to the
patient should be clearly identified »
It precludes automatic
substitution
NATIONAL COMPETENCES
Automatic
substitution not
allowed
France, Germany,
Greece, Italy,
Slovenia, Spain,
Sweden, UK
Automatic
substitution must
be actively
prohibited by the
physician
Czech Republic
Official list stating
which products
cannot be
substituted
Denmark, Finland,
Hungary, Norway,
Slovakia
Physicians obliged
to prescribe by
brand name
Austria
21
Should a generic company invest on
biosimilars?: conclusion
Strengths
Weaknesses
Development cost and
duration compared with a
« full dossier »
 Patents expiring
Limited experience
 Devlopment Cost and
duration compared with
generics
 Substituability

Opportunities
Biologicals market size
 Future patents expiry
 Experience improvement
 Low prices will influence
physician's prescription


SWOT
Threats
Innovators experience
 Bad physicians’ point of
view

22
3rd part:
DEVELOPMENT
OF A hCG
BIOSIMILAR
23
Human Chorionic Gonadotrophin
(hCG)
•Glycoprotein hormone
•Heterodimeric structure: 2 sub-units non covalently associated (held
by hydrophobic forces)
• 1 sub-unit α : 93 amino acids
Common to LH, FSH, TSH
• 1 sub-unit β : 145 amino acids
Confers the biological specificity of
the hormone
24
Human Chorionic Gonadotrophin
(hCG)
Mechanism of action:
LH/CG-R
(granulosa cells and theca cells)
25
Human Chorionic Gonadotrophin
(hCG)
1° Oocyte meiosis
resumption
follicular rupture
Ovulation
triggering
2° promotes the maintenance of
the corpus luteum during the
beginning of pregnancy
http://openlearn.open.ac.uk/mod/oucontent/view.php?id=398496&sectio
n=1.3.5
Progesterone and
estradiol secretions
enriches the uterus with a
thick lining of blood vessels
26
Drugs Containing hCG
Urinary hCG
PREGNYL®
Recombinant hCG
OVITRELLE ® (E.U)/
OVIDREL ® (US)
PROFASI ®
NOVAREL ®
 Two questions can be asked
27
1.Which drug to take as the reference product to compare?
« The reference product must have a
MA in the E.U and must be
manufactured in the E.U »
(Overall guideline on B.S)
Pregnyl® and
Ovitrelle ® OK
2.Comparison with the urinary form or the recombinant form?
No specific information in the
guidelines : consultation with
EMA would be needed
28
Identity Card
• MA : 02/02/2001 (Centralised
Procedure)
• 250µg of Choriogonadotropin
alfa (6500 IU)
• Subcutaneous administration
• Manufacturing process:
recombinant DNA technology
Indications
1) Adult women undergoing
superovulation prior to assisted
reproductive techniques such as in
vitro fertilisation (IVF)
2) Anovulatory or oligoovulatory
women
Posology
One vial of Ovitrelle ® 24 to 48 H after the last
administration of a follicle stimulating hormone (FSH), i.e.
when optimal stimulation of follicular growth is achieved.
29
Patents
1° Method of production: (January 1993)
“Recombinant heterodimeric human fertility hormones, and methods,
cells, and vectors and DNA for the production thereof ”
Invention claimed: « when both subunits are produced in the same cell, a
hormone is expressed which is biologically active”
01/93
Patent filed
02/01
M.A
01/13
End of
patent
02/16
End of CCP = entry of
Biosimilars
30
Patents
2° hCG Formulation:
“We have surprisingly found that it is possible to
obtain liquid stabilised formulations”
Invention claimed: liquid pharmaceutical composition containing
hCG stabilised with a polyalcohol (mannitol) or a non-reducing
sugar (sucrose)
Simplifies the way of use (avoid the reconstitution of lyophilised powder)
And allows auto-injections with pre-filled pens
Problem : patent expiry = 2021
The patent has to be challenged!
31
Which Guidelines to rely on ?
Overarching Guideline
CHMP/437/04 (under revision)
Quality
BWP/49348/05 (Under revision)
General
Non-clinical / Clinical
BMWP/42482/05 (under revision)
Insulin
Somatropin
Epoetin
FSH
Hep
GCSF
IF alfa
Specific
IF beta
Original
Revised
New
Under revision
Mo Ab
No specific guidelines for
our product
32
What studies to perform?
REFERENCE BIOLOGICAL
MEDICINAL PRODUCT
(Ovitrelle®)
N.B : « the same reference
product must be used for all 3
parts of the dossier »
SIMILAR BIOLOGICAL
MEDICINAL PRODUCT
33
QUALITY STUDIES
34
Quality studies
A full Quality dossier:
CTD Module
3
+
Comparability
exercise
Key point all
along the
dossier!!
35
Which process to use?
HOST
CELLS
Procaryotic
cell (e.g E. coli)
Eucaryotic
cell
Our protein of interest is glycosylated :
needs post-traductional modifications
Yeast cell
Mammalian cell
Chinese Hamster Ovary
We have a better chance to reach the reference
API quality by using the same host cells
36
Process
Organism
naturally
expressing the
protein of
interest
Genes of
interest
Wild
vector
α unit gene
β unit gene
Expression
vector
hCG
Genetically
modified CHO
expressing
the protein of
interest
r-hCG
37
Structural comparison
Main risk:
Biosynthetic
process
Inherent
diversity of
structural
heterogenicity
Possible diversity
in the
glycosylation
profile
hCG : highly glycosylated
protein
GL: « given the complexity of the
molecule and its inherent
hetorogenecity, the set of analytical
techniques should represent the
state-of-the-art »
38
Structural comparison
Example:
Structural comparison of a marketed FSH (Gonal-f®) and its biosimilar
Identical polypeptide chains
But
Different glycosylation pattern
( higher % of tri- and tetraantennary glycans)
Glycosylation influences pharmacokinetics and
may influence efficacy and safety
39
Example: Evaluation of
BINOCRIT® (EPO biosimilar)
compared to the reference
EPREX®
EPO = Glycoprotein :
165 amino acids
3 N-glycans
1 O-glycan
EPAR: “Minor differences were observed at the glycosylation
level but comparability was proved”
GL:« Minor structural differences in the active substance, such as
variability in post-translational modifications may be acceptable. »
Depending on the Nonclinical and Clinical results
40
Impurities
desired
product
??? PROFILE Peptide
variants
Post-traductionnal
variants
degradation
IMPURITY PROFILE
Process and
product- related
impurities
41
Impurities
Product-related impurities
• oxydation
• dissociated subunits
• aggregates
GL: « The product-related
substances and impurities in the
Biosimilar should be identified and
compared to the reference
product »
Process-related impurities
•residual DNA
• host cell proteins and
culture medium proteins
• microbial/viral
contaminations
• bacterial endotoxins
GL: « The process-related impurities
are expected to differ from one to
another process: their comparison
may not be relevant »
Non clinical and clinical studies to perform will be
determined by the level of differences of impurities
between the 2 products
42
REFERENCE
BIOLOGICAL
MEDICINAL PRODUCT
(Ovitrelle®)
SIMILAR BIOLOGICAL
MEDICINAL PRODUCT
43
NON CLINICAL
STUDIES
44
Pharmacodynamic studies
a) In vitro bioassays
To establish comparability in reactivity
Tools:
Primary granulosa cells
Permanently cultured cells
Advantages
•LH/CG Receptor is
investigated in its natural
context
• provides enough material
Drawbacks
• Limited number of cells
• relies on artificial construct
LH/CG-R
MA-10 cells
45
Pharmacodynamic studies
- Binding assays
Expected results:
MA-10 cell
Binding constant Ovitrelle
=
Binding constant Biosimilar
Ovitrelle® or Biosimilar
- Potency
Progesterone
MA-10 cell
Ovitrelle ® or Biosimilar
Expected results:
[Progesterone] with Ovitrelle
=
[Progesterone] with Biosimilar
46
Pharmacodynamic studies
b) In vivo bioassays
in vitro studies may not fully reflect the more complex
situation in vivo
additional comparative in vivo studies should be performed.
Tests on adult female monkeys. For both products, we
should see:
• the production of oocytes of the same maturity
• the same hormonal activities on luteinisation of
ovarian follicles
• identical time course of action
47
Toxicological studies
Single dose
toxicity –
SC
(rats and
monkeys)
No expected
effects
Repeat Dose
toxicity –
SC
(rats and
monkeys)
Expected effects:
• Hormonal disturbances
(smaller testes,
enlargement of the
ovaries…)
+ search of antibodies to r-hCG
GL:« Normally, other routine toxicological studies (safety
pharmacology, reproduction toxicology, mutagenicity and
carcinogenicity studies) are not required for biosimilars.»
48
REFERENCE
BIOLOGICAL
MEDICINAL PRODUCT
(Ovitrelle®)
SIMILAR BIOLOGICAL
MEDICINAL PRODUCT
49
CLINICAL STUDIES
50
Clinical studies
In accordance with Guideline on non-clinical and clinical
development of similar biological medicinal products
containing recombinant human follicle stimulating
hormone (r-hFSH)
&
Guideline Similar biological medicinal products
containing biotechnology-derived proteins as active
substance: non-clinical and clinical issues
51
Aim of these studies : Non inferiority and Non superiority !
52
Pharmacokinetic studies
 Single dose, steady state or repeated determination
of PK parameters :
 Administration SC :
Single dose
Ovitrelle ® : 250 µg
BioS :250 µg
 Dosage :
Radioimmunoassay
53
GL: “The pharmacokinetic parameters of interest are
AUC, cmax, tmax, t1/2 and clearance. For the AUC and
cmax, the 90% confidence interval of the ratio
test/reference should lie within the acceptance range of
80% to 125%”
 AUC and Cmax
absorption/bioavailability
about 40 %
differencies in elimination
half life elimination = 30 h
Accepted range 80-125%
54
Pharmacodynamic studies
 Biosimilar vs Reference in a revelant population in order to
demonstrate therapeutic efficacy of the product : 12 healthy
volunteers
6 female volunteers
under oral contraceptive
Ovarian supression
Ovitrelle® 250 µg
Biosimilar 250 µg
6 male volunteers
previously
pituitary
down-regulated
55
Pharmacodynamic studies
measuring androstenedione and testosterone
exogenous administration after pituitary/ovarian downregulation is capable of initiating the aimed effect of
stimulation of the testes/ovaries, as shown by the
increase in testosterone
GL: The pharmacodynamic (PD) markers should be selected on the basis of their
relevance to demonstrate therapeutic efficacy of the product. The pharmacodynamic
effect of the test and the reference medicinal products should be compared in a
population where the possible differences can best be observed
56
 If results are comparable to the Reference :
Efficacy Trial
 If it’s not comparable to the Reference :
Full Development
with a complete dossier
No biosimilar product
 If results tend to be comparable:
Study PK/PD
57
PK/PD
Best conclusion :
PD effects produced by both Biosimilar and Reference are similar
and this further supports PK bioequivalence
58
Efficacy trials
 Study Phase III: multicentre trials, double blind,
randomised
 200 FIV
 Primary parameter  oocytes retrieved
 Secondary parameters  oocyte maturity and quality,
fertilisation, implantation and pregnancy
GL: “Usually comparative clinical trials will be necessary to
demonstrate clinical comparability between the similar
biological and the reference medicinal product”
59
Efficacy trials
Major inclusion criteria
Major exclusion criteria
Infertility
Systemic disease
20-38 years old
Polycistic ovarian syndrom
Presence of both ovaries
Previous OHSS
No more than 3 previous assisted
conception cycles
Previous IVF failure
Aim : 11 +/- 3 oocytes retrieved
60
If the biosimilar shows adequate comparability to the innovator product for
one indication, it may be reasonable to extend the approval of the biosimilar
to all the indications of the innovator product
 Ex : Omnitrope®
Comparability studies between Omnitrope® and the reference product
(Genotropin®) were conducted only in children with growth disturbances
Omnitrope® including the indication for use in adults
 Reasons for the extrapolation :
(1) the long clinical history of safe use of growth hormone;
(2) the wide therapeutic window of the drug;
(3) the rarity of reports of neutralizing antibodies;
(4) the ability to characterize the structure and biological activity of growth
hormones by physicochemical and biological methods
(5) the variety of assays available to characterize the active and product-related
substances
61
Clinical safety
GL: Data from the efficacy trial will usually be sufficient to characterize the adverse
event profile of the biosimilar product
 Monitoring adverse events during efficacy trials
 Focus on well-known adverse events like OHSS : Ovarian HyperStimulation
Syndrom (2%)
Symptoms : urination significantly darker, calf and chest pains, ascites…
Symptoms generally resolve in 1 to 2 weeks, but will be more severe and persist longer
if pregnancy occurs
Complications:ovarian torsion, ovarian rupture,
thrombophlebitis and renal insufficiency
Treatment : aspiration ascites, electrolytes
62
Clinical safety

-
The most common side effects are:
general disorders (headache, tiredness)
gastro-intestinal system disorders (vomiting/nausea, abdominal pain)
application site disorders (local reaction/pain at injection site)
 Uncommon side effects are:
- psychiatric disorders (depression, irritability, restlessness)
- gastrointestinal system disorders (diarrhoea)
And …
 Measurements of antibodies before and after treatment
(immunogenicity evaluation)
 Post-treatment visit (15-17 days after treatment)
63
Immunogenicity
 Ovitrelle®  no immunogenicity demonstrated
 Biosimilar :
 Hyp 1: all patients tested for anti-hCG antibodies after a
single dose were negative
not immunogenic
 Hyp 2 : anti-hCG antibodies found
immunogenicity
Immunogenicity is more likely to occur when the
therapeutic protein is given intermittently than
continuously
and the subcutaneous route of administration is more
immunogenic than the intravenous one
64
REFERENCE
BIOLOGICAL
MEDICINAL PRODUCT
(Ovitrelle®)
SIMILAR BIOLOGICAL
MEDICINAL PRODUCT
65
POST-MARKETING
ACTIVITIES
66
Pharmacovigilance

2 safety issues to distinguish
 Product specific: linked to differences in the process
 Therapeutic class specific
GL: “risk management plan or
pharmacovigilance plan must be
submitted, taking into account risks
identified during product
development and potential risks”
 Clinical trials were performed considering only one indication: safety must be
certified for both
GL: “it is important to consider the
risk of immunogenicity in different
therapeutic indications separately”
67
Risk management plan
 What to take into account: Refer to FSH Guideline:
GL: “The risk management plan
should include identified and
potential risks associated with
the use of r-hFSH containing
medicinal products”
Immunogenicity
OHSS
Critical points to be
monitored
68
Global rules for Pharmacovigilance
 An adverse reaction report for any biological drug
should always include :
 full name of the biological drug
 batch number
Naming rules
69
Naming
Overall GuideLine: « In order to support
PharmacoVigilance monitoring, the
specific medicinal product given to the
patient should be clearly identified »
“The name, appearance, and
packaging of a biosimilar medicine
should differ from those of the
reference product “
One biosimilar = one brand name
Licit, Distinctive & Available
Only one submission in UE
(OHMI) in class 5
10-15 proposed
names
70
Naming
 6 Proposed names to EMA:
- Procreal®
- Procrealine ®
- Gonadoline ®
- Fecondial ®
- Fecondialine ®
maximum 3 of them in accordance
with NRG criteria & the GUIDELINE ON
THE ACCEPTABILITY OF NAMES FOR HUMAN
MEDICINAL PRODUCTS PROCESSED THROUGH
THE CENTRALISED PROCEDURE
- Chorial ®
Waiting for authorities’ decisions
Fecondialine®
71
PRICING ISSUES
72
How can we fix the cost of a biosimilar?
3 main points to consider:
1. Duration and cost of the development
Up to 8 years and at least € 100 Millions
Source: Lonza, Teva
73
How can we fix the cost of a biosimilar?
As a comparison:
Chemical generic drugs
1 – 10 € Millions
Biosimilar
> 100 € Millions…
... + Additionnal costs:
• Institution of a Pharmacovigilance plan
• Recruiting sales forces
Convince skeptikal physicians that the Biosimilar
is as « good » as the reference product.
Ex : Gynaecologists for the Biosimilar of Ovitrelle®
Fixed costs for Biosimilars are much higher than for
chemical generic drugs !
74
How can we fix the cost of a biosimilar?
2. Cost of manufacturing
Huge investments in Biosimilars manufacturing processes
compared to those for generic synthetic drugs
75
How can we fix the cost of a biosimilar?
3. Number of competitors on the market
Limited number of Biosimilars
manufacturers:
Sandoz
Teva…
Vs.
Large number of Generics
manufacturers:
Ex in France: (Biogaran, Alter, Arrow,
EG, Mylan, Sandoz…)
One year after the entry of the 1st Biosimilar/Generics
manufacturer, it is estimated that there will be on the market:
2 Biosimilar manufacturers
Vs.
9 Generic manufacturers
76
Entry and Competition in Generic Biologics (Henry G. Grabowski*, David B. Ridley and Kevin A. Schulman)
How can we fix the cost of a biosimilar?
Taking into consideration these 3 points:
Discounts on Biosimilars will not be as high as for chemical Generics
Maximum discounts observed in the E.U after 2 years of Marketing:
Biosimilar
Entry and Competition in Generic Biologics (Henry G. Grabowski*, David B. Ridley and Kevin A. Schulman)
Chemical
Generic
77
How can we fix the cost of a biosimilar?
Example of Somatropin Biosimilar:
= 36,11 €
Targeted price for our
Biosimilar =
28,50€
78
Public health expenditures
EMA estimation : BS generated annual savings of
1,4 billion euros in the E.U in 2009
NICE Decision in May 2010: Omnitrope : 1st Biosimilar recommended
« When more than one product is suitable, the least costly option should be chosen »
Cost difference
Effectiveness difference
Biosimilars should have their points on this axis
79
Ovitrelle® biosimilar: best choice?
A.S
Choriogonadotrophin alfa
Administration
Structure
SC (auto-injections)
Highly Glycosylated protein
Follitropin alfa
SC (auto-injections)
Highly Glycosylated protein
Same Quality concerns
Number of ind.
2
4 (3 for women + 1 for men)
Specific guidelines?
NO
YES
Revenues in 2010
45 millions €
504 millions €
80
Conclusion
At the end of the development, can we answer to our previous issues?

How can the level of similarity be well established ?
Comparability
exercise
Quality
Safety
Clinical efficacy-safety
• How can the risks associated be defined ?
Cannot be fully defined during Pre-authorisation development
Importance of PV and MRP
How similar is similar enough ?
What about a full dossier?
81
Thanks for your
attention!
82