Transcript Introduction to Biosimilars

Introduction to
Biosimilars
Presented by:Dr/Kholoud Mamdouh
Biologicals Marketing Authorization Directorate
Central Administration for Pharmaceutical Affairs
www.eda.mohealth.gov.eg
[email protected]
Biosimilar concept (Q,S and E pov)
Pharmaceutical product
Innovator
Generic
Biosimilars
are not
generics
Biological product
Innovator
Biosimilar
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EMA concept
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EMA concept
Generic
• The applicant is not required
to provide the results of pre-
clinical tests and clinical
trials if he can demonstrate
that the medicinal product is a
generic medicinal product of a
reference medicinal product
which is or has been authorised
a Member State or in the Union
• A generic medicinal product is
defined as a medicinal product
that has:
• the same qualitative and
quantitative composition in
active substance(s) as the
reference product,
• the same pharmaceutical form
as the reference medicinal
product,
• and whose bioequivalence
with the reference medicinal
product has been
demonstrated by appropriate
bioavailability studies.
Hybrid
•differ from generic
applications in that the
results of appropriate preclinical tests and clinical
trials will be necessary in
the following three
circumstances:
•In case were the medicinal
product doesn’t fall in
definition of a ‘generic
medicinal product’
•where the bioavailability
studies cannot be used to
demonstrate
bioequivalence;
•where there are changes in
the active substance(s),
therapeutic indications,
strength, pharmaceutical
form or route of
administration of the generic
product compared to the
reference medicinal
product.
Biosimilar
•A biosimilar medicine is a
biological medicine that is
developed to be similar to
an existing biological
medicine (the ‘reference
medicine’).
•The active substance of a
biosimilar and its reference
medicine is essentially the
same biological substance,
though there may be minor
differences due to their
complex nature and
production methods. Like the
reference medicine, the
biosimilar has a degree of
natural variability. When
approved, its variability and
any differences between it
and its reference medicine
will have been shown not to
affect safety or effectiveness.
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Similar Versions
Generic
Vs
Biosimilar
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Generic Vs Biosimilar
Innovator
sameness
profile
Quality
Complete and
independant product
information
Preclinical
Complete preclinical
studies
Clinical
Complete clinical
studies
Generic
Biosimilar
A generic drug is
identical to a brand
name drug in dosage
form, safety, strength,
route of administration,
quality, performance
characteristics and
intended use
A biosimilar product is similar to a
reference biological product in
the active substance, dosage
form, Strength and route of
administration and proved that its
quality, safety and efficacy is
similar to a reference biological
product when prescribed in a
claimed indication
Complete and
independant product
information
meet the same
specifications as brand
Complete and independant
product information with
comprehensive comparability
with reference
Reduced preclinical
comparability
-In vitro PD
- In vivo repeat dose toxicity
Bioequivalence study
Reduced clinical comparability
-Phase 1 PK/PD
Phase III
- Immunogenicity
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Chemical Vs Biological
• Aspirin Vs Monoclonal antibody
Source: New England Journal of Medicines, “Developing the Nation’s Biosimilars Program,” August 4, 2011
Chemical Vs Biological
Chemical
Biological
Product
characteristic
Small, simple molecule
Large complex molecules,
Higher order structures, post
translational modifications
Production
Produced by chemical
synthesis
Produced from biological
origin
Analytical testing
Well defined chemical
structure
Heterogenous, difficult to
characterize
Process
dependence
Not sensitive to
manufacturing process
changes
Sensitive to minor changes in
manufacturing process
Identity and purity
Often meeting
pharmacopeia or other
standards of identity
Most have no pharmacopeia
monographs
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Product is the process
The Rule in Biologicals
The product is the process
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Guidelines for changing the process
Guidelines addressing the changes in the
manufacturing process for biological product
FDA (April 1996)
Guidance for Industry
Comparability Protocols Protein
Drug Products and Biological
Products - Chemistry,
Manufacturing, and Controls
Information
ICH (June 2005)
Comparability of
biotechnological/biological
products subject to changes in
their manufacturing process
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Comparability of biotechnological/biological products
subject to changes in their manufacturing process
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Comparability of biotechnological/biological products
subject to changes in their manufacturing process
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Guidance for Industry Comparability Protocols Protein Drug Products
and Biological Products - Chemistry, Manufacturing, and Controls
Information
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Problems issued from changing process of
Epotin alfa
Eprex formulations
With Human serum albumin (HSA)
With Polysorbate 80 (Tween )
Diagnosis EPO antibody
mediated PRCA cases
•Unexplained loss of effect
(LOE)
• Anaemia (Hb decreases by
about 0.1 g/dl/day)
• Low reticulocyte count (<
10 000/μl)
• Platelets. White blood cells :
normal
• Bone marrow (strongly
recommended)
– Normal cellularity
– Erythroblasts very rare (< 5
%)
• Positive Epo antibody test
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Change in formulation
Immune-response and adverse reactions: PRCA case example Nicole Casadevall - EMA
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Change in formulation continue
The interaction of Tween and the uncoated rubber in pre-filled syringes
appears to cause leachates. These leachates have been implicated in
causing aggregation of epoetin molecules that then enhance their
antigencity.
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Biosimilars guidance world wide
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Biosimilars guidance world wide
Health Authority
Date of guidance release
EMA
2005
WHO
2009
MHLW(Japan)
2009
HC
2010
KFDA
2010
FDA
Draft 2012
SFDA
2012
CDSCO (India)
2012
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EMA (Biosimilars)
• First guide line 2005
• Scope:
In principle, the concept of
similar biological medicinal
product is applicable to
any biological product.
However, in practice, the
success of such a
development approach
will depend on the ability to
characterise the product
and therefore to
demonstrate the similar
nature of the concerned
product
• Reference
• Should be licensed in EMA
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Approved EMA Biosimilar Products
Product Name
Manufacturer/Company Name
Active
Substance
epoetin alfa
Authorisation
Date
28 Aug 2007
Binocrit
Biograstim
Epoetin alfa
Hexal
Filgrastim Hexal
epoetin alfa
Filgrastim
epoetin alfa
28 Aug 2007
15 Sep 2008
28 Aug 2007
Medice Arzneimittel Pütter GmbH
& Co KG
Sandoz GmbH
CT Arzneimittel GmbH
Hexal AG
Filgrastim
6 Feb 2009
Hexal AG
Filgrastim
ratiopharm
Filgrastim
15 Sep 2008
Withdrawn on
20 Apr 2011
Ratiopharm GmbH
Nivestim
Omnitrope
Ratiograstim
Retacrit
Silapo
Tevagrastim
Valtropin
Zarzio
Filgrastim
Somatropin
Filgrastim
epoetin zeta
epoetin zeta
Filgrastim
Somatropin
filgrastim
8 Jun 2010
12 Apr 2006
15 Sep 2008
18 Dec 2007
18 Dec 2007
15 Sep 2008
24 Apr 2006
6 Feb 2009
Hospira UK Ltd
Sandoz GmbH
Ratiopharm GmbH
Hospira UK Ltd
Stada R & D AG
Teva Generics GmbH
BioPartners GmbH
Sandoz GmbH
Abseamed
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FDA (Biosimilars/Follow-on protein)
FDC Act
section 505
(ANDA) process
in section
505(j)
pathway
described in
section
505(b)(2)
Generic
drugs
Follow on
proteins
PHS Act
Section 351
Ammendment
BPCI Act
Biosimilars
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Follow-On Protein Products: Regulatory and
Scientific Issues Related to Developing
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FDA (Follow on proteins)
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FDA (Follow on proteins)
The Agency indicated its intention to issue guidance documents to specifically
address human growth hormone and insulin. But, as our knowledge of this issue
expanded, we reconsidered our focus and determined it would be more
appropriate to initially promulgate guidance that is more broadly applicable to
follow-on protein products in general. We are in the process of developing such
guidance with respect to products approved under the FDC Act (updated 7/2009)
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Approved follow-on proteins in FDA
FDA (Follow on
protein)
• Hylenex (hyaluronidase
recombinant human)
• Hydase (hyaluronidase)
• Fortical (calcitonin salmon
recombinant) Nasal Spray
• Amphadase
(hyaluronidase)
• GlucaGen (glucagon
recombinant for injection)
• Omnitrope (somatropin
[rDNA origin])
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Case Study: Omnitrope
Omnitrope is the first recombinant human growth hormone product approved
through the abbreviated pathway, Specifically, the approval was based on the
following:
Physicochemical testing that established, among other things, that the structure of the active
ingredient in Omnitrope is highly similar to the structure of the active ingredient in Genotropin;
New non-clinical pharmacology and toxicology data specific to Omnitrope;
Vast clinical experience and a wealth of published literature concerning the clinical effects
(safety and effectiveness) of human growth hormone;
Pharmacokinetic, pharmacodynamic, and comparative bioavailability data that established,
among other things, that Omnitrope and Genotropin are highly similar based on pharmacokinetic
parameters and pharmacodynamic responses;
Clinical efficacy and safety data from controlled trials comparing Omnitrope to Genotropin and
from long-term trials with Omnitrope in pediatric patients; and
FDA's conclusions that Genotropin is safe and effective for the indications for which approval was
sought in the Omnitrope application and that Omnitrope is highly similar to Genotropin.
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FDA (Biosimilars)
Scope:
The guidance focuses
on therapeutic protein
products
Protein means any
alpha amino acid
polymer with a specific
defined sequence that
is greater than 40
amino acids in size.
Reference:
Should be licensed in
US
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WHO (Similar Biotherapeutic Products SBPs)
• Scope:
• Applies to well-established
•
and well-characterized
biotherapeutic products
such as recombinant
DNA-derived therapeutic
proteins.
Vaccines, plasma derived
products, and their
recombinant analogues
are excluded from the
scope
• Reference:
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Health Canada (Subsequent Entry Biologic SEBs)
• Scope:
• The guidance applies to
biologic drugs that contain,
as their active substances,
well characterized proteins
derived through modern
biotechnological methods
such as use of recombinant
DNA and/or cell culture
• Canadian Guidelines
shares the similar concept
of the WHO
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Korean FDA (Biosimilars)
• Scope:
Similar to EMA Concept
• Reference:
•
should be a biological
product authorized in Korea.
Preclinical and Clinical
aspects
Similar to WHO
CDSCO (Indian) (Similar Biologic)
• Scope:
• , well characterized
•
•
proteins derived through
modern biotechnological
methods such as use of
recombinant DNA
technology
Rerefence:
Registrered in
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Thank You