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Tuesday, 19 November, 2013 Latin America Biotherapeutic Conference Day 1
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Dr. Karin Heidenreich / Global Public Policy R&D
Novartis International AG, Switzerland
Workshop on Biotherapeutics & Biosimilars
Lima/Peru on 19 November 2013
Biosimilars: Principles of their Development and Evaluation
Disclaimer
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particular, management's expectations could be affected by, among other things, unexpected regulatory actions or delays or government
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Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual
results may vary materially from those described herein as anticipated, believed, estimated or expected. Novartis is providing the
information in this presentation as of this date and does not undertake any obligation to update any forward-looking statements as a result
of new information, future events or otherwise.
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Table of Contents
Key Principles of Biosimilar development
• What is a Biosimiliar?
• Differences to Generic Medicines
• Development via a Two-Step Procedure
Overview of international Guidance on Biosimilars
Novartis Position on Biosimilars
Summary and Regulatory Needs
3 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
Table of Contents
Key Principles of Biosimilar development
• What is a Biosimiliar?
• Differences to Generic Medicines
• Development via a Two-Step Procedure
Overview of international Guidance on Biosimilars
Novartis Position on Biosimilars
Summary and Regulatory Needs
4 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
Different types of biologics in circulation Not every version of a biologic is a biosimilar
Originator Biosimilar Non-
comparable
Counterfeit
medicine
• First registration
of new molecule
• Approval based
on demonstrated
quality, safety
and efficacy
• Version of
registered original
biologic
• Approval based on
extensive
comparability
exercise via special
and stringent
registration pathway
(e.g. in EU)
• Patients can expect
same clinical profile
as with originator
• Questionable copy
of registered original
biologic
• Approval not based
on demonstrated
comparability
without special
registration pathway;
sometimes stand-
alone application
• Patients cannot
expect the same
clinical profile as
with originator
• Illegal copy version
of registered
original biologic
• Biological and
pharmaceutical
quality unclear,
mostly substandard
or even harmful
5 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
Different types of biologics in circulation Not every version of a biologic is a biosimilar
Originator Biosimilar Non-
comparable
Counterfeit
medicine
• First registration
of new molecule
• Approval based
on demonstrated
quality, safety
and efficacy
• Version of
registered original
biologic
• Approval based on
extensive
comparability
exercise via special
and stringent
registration pathway
(e.g. in EU, USA,
Canada, Australia)
• Patients can expect
same clinical profile
as with originator
• Questionable copy
of registered original
biologic
• Approval not based
on demonstrated
comparability
without special
registration pathway;
sometimes stand-
alone application
• Patients cannot
expect the same
clinical profile as
with originator
• Illegal copy version
of registered
original biologic
• Biological and
pharmaceutical
quality unclear,
mostly substandard
or even harmful
6 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
What is a Biosimilar?
Definition proposed by EMA in draft guideline on „similar biological medicinal products‟1:
A biosimilar is a biological medicinal product containing a version of the active substance of an already authorised original biological medicinal product (reference medicinal product).
A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise.
7 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
1 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500142978.pdf
Differences between Generics and Biosimilars
Same qualitative and quantitative composition in active substances and the same pharmaceutical form as the referenced originator product
Abbreviated dossier: own quality information, demonstrated bioequivalence as well as referring to the established safety and efficacy data of the reference product
Generics and reference product are usually interchangable/substitutable
A version of the active substance of an already authorized original biological medicinal product
Demonstrates similarity to the reference product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise
Patients can expect the same clinical outcomes from a biosimilar and the originator drug
Expiry of patent and
other exclusivities
Small
molecules
Original
biologics
Generics Biosimilars
8 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
Development of high-quality biosimilars is a systematic and robust process with two key steps
Phase I Phase III
Develop highly similar product Confirm biosimilarity
Drug substance
Formulation / Drug product
GLP Tox.
Process validation
Technical development to achieve a
“highly similar” molecule, which
matches the quality attributes of the
reference product
Demonstration of structural and
functional similarity
Targeted non-clinical and clinical
program to demonstrate similarity
Scope depends on similarity in quality
attributes and requires agreement
with health authorities
Step 1 Step 2
9 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
Step 1: Variability of the reference product defines the target
Manufacturing changes lead to
more pronounced shifts
• Manufacturing changes are made
frequently
• Changes in the manufacturing process
generate slightly different versions of the
originator molecule
• These shifts usually have no implication
for clinical function
• Non-identicality is a normal principle in
glycosylated proteins
• No batch of any biologic is “identical” to
the other batches
• Low variability is natural and generally not
problematic for clinical outcome
Biologic products vary from batch
to batch
Batch of drug substance (DS)
Bio
log
ica
l Activity (
Units/m
g)
0,0
0,4
0,8
1,2
1,6
2,0
08.2007 12.2008 05.2010 09.2011
Expiry Date
Unfucosylated G0
[% of glycans]
60
80
100
120
140
08.2007 12.2008 05.2010 09.2011
Expiry Date
ADCC Potency
[% of reference] Post-
Shift
Pre-Shift
Pre-Shift
Post-
Shift
Schneider, C. K.: Biosimilarity: A better definition of terms and
concepts. 25th Annual DIA EuroMeeting, 04-06/03/2013, Amsterdam
Schiestl, M., et al.: Acceptable Changes in Quality Attributes of Glycosylated
Biopharmaceuticals. Nature Biotechnology, 29 (4): 310-312, 2011
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Biosimilars are approved biologics with comparable Q, S and E to a reference product
Sample E IA IB IIA IIB IIIA IIIB IV V VII VIII E
Schellekens H et al. Eur J Hosp Pharm Pract 2004;3:43–7
Non-comparable “copy biologic” ≠ biosimilar
NOT similar to Reference E
Brockmeyer C & Seidl A et al. Eur J Hosp Pharm
Pract 2009;15:34–40
Approved biosimilar in EU
Sample 1 2 3 4
NO difference to originator
• Developed and manufactured using state-of-the-
art technology
• Demonstrated comparable quality (Q), safety (S),
and efficacy (E) to a reference product
• Approved via stringent regulatory pathways
• Non-comparable or alternative copy biologics are
NOT biosimilars
• Have not demonstrated biosimilarity via a state-
of-the-art comparability exercise
• Not approved following a specific biosimilars
registration pathway (e.g. in line with WHO
recommendations)
What is a biosimilar?
What is NOT a biosimilar?
11 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
Step 2: Demonstration that no meaningful difference in clinical profile can be expected
Targeted non-clinical and clinical program with indication and endpoints most sensitive to detect differences; no re-demonstration of safety and efficacy
Extrapolation to other indications of the reference product should be possibile and justified based on the “Totality-of-Evidence”, including:
• High level of structural (as demonstrated by physicochemical characterization) and functional (as demonstrated by in vitro biological assays) similarity
• Similarity regarding pharmacokinetics in humans
• Similar efficacy and safety in a single, most sensitive indication (immunogenicity)
• Same mode-of-action of indications (if known)
Immunogenicity data should be always required for all biologics, including biosimilars
Risk management plans for post-licensing surveillance should be routinely required for all new drugs, including biosimilars
| Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only 12
Illustration of the difference between originator and biosimilar development
The world
turned upside
down....
Originator
development
Biosimilar
development
Clinical
studies
PK/PD
Non-clinical
Analytical Analytical
Non-clinical
PK/PD
Additional clinical studies
Source: modified slide shown by EGA at EMA Workshop in London on 31 Oct 2013
Comparison
with the
reference
product
Main focus of the originator development program is on clinical studies; for the
biosimilars on the analytical studies
The purpose of the clinical program of the biosimilar is to confirm similarity of
efficacy and safety to the reference product, not to re-establish efficacy and safety
Therefore, design and endpoints of the clinical studies conducted with the
biosimilar are different
Table of Contents
Key Principles of Biosimilar development
• What is a Biosimiliar?
• Differences to Generic Medicines
• Development via a Two-Step Procedure
Overview of international Guidance on Biosimilars
Novartis Position on Biosimilars
Summary and Regulatory Needs
14 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
Provides globally acceptable principles1 for licensing of biotherapeutic products that are claimed to be similar to original biotherapeutic products:
• “A SBP is intended to be similar to a licensed biotherapeutic product for which there is a substantial evidence of safety and efficacy. The ability for the SBP to be authorized based on reduced non-clinical and clinical data depends on proof of its similarity to an appropriate RBP through the comparability exercise.”
• “Comprehensive characterization and comparison at the quality level are the basis for possible data reduction in the non-clinical and clinical development.”
• “Significant differences between the SBP and the chosen RBP detected during the comparability exercise would be an indication that the products are not similar and more extensive non-clinical and clinical data may be required to support the application for licensing.”
15 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
WHO – 2009 Guidelines on evaluation of similar biotherapeutic products (SBPs)
1 http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf
European Medicines Agency: Well-established regulatory framework for biosimilars (2005)
Legal basis
• Directive 2001/83/EC as amended, Art 10(4)
• Multiple general and product specific guidelines that are regularly updated (refer to next slide)
Main principles
• Regulatory pathway structured like the process to approve originators after significant manufacturing change
• Two-step approach to demonstrate similarity to reference product
• Extrapolation across indications possible under justified conditions
• Use of non-European reference product for partial demonstration of similarity based on bridging studies
• Acceptance of same INN and a label that allows the healthcare professional to make a treatment decision
• No statement on interchangeability/substitutability; competence with the national governments
| Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only 16
European Medicines Agency EU Guidelines for Biosimilars
General Other Product-specific
Quality
Non-clinical
Clinical
“Overarching”
Risk Management
Plan
Immunogenicity
assessment of
biotech products
Somatropin
Epoetin
G-CSF
Insulin
LMWH
Interferon alfa
G-CSF: Granulocyte-colony stimulating factor (filgrastim or lenograstim); LMWH: Low Molecular Weight Heparin; *Concept paper
Monoclonal
Antibodies
Interferon beta
Follicle Stimulation
Hormone
Statistical methods
for comparability in
quality attributes*
General Biosimilar
Brochure
Q&A Document
17 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
US Food and Drug Administration
Legal basis
• Patient Protection and Affordable Care Act (Affordable Care Act), of 2010
• Biologics Price Competition and Innovation Act (BPCI Act) creates an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product
• A number of (draft) guidance documents1
Main principles
• Licensed biosimilar and interchangeable biological products will have to meet the Agency‟s exacting standards of safety and efficacy
• Risk-based “totality-of-the-evidence” approach in support of a determination of biosimilarity of the proposed product to the reference product via a stepwise approach in the development of biosimilar products
• Distinction of „biosimilar products‟ and „interchangeable biosimilar products‟
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1 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologic
Applications/Biosimilars/
Table of Contents
Key Principles of Biosimilar development
• What is a Biosimiliar?
• Differences to Generic Medicines
• Development via a Two-Step Procedure
Overview of international Guidance on Biosimilars
Novartis Position on Biosimilars
Summary and Regulatory Needs
19 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
Novartis develops both, innovative medicines and biosimilars of high quality
Environment Patient needs Novartis portfolio
Pharmaceuticals
Vaccines and
Diagnostics
Sandoz (Generics) Full range
of healthcare options
Innovative medicines
Prevention
Affordable options
Self-care
Alcon
(Eye care)
OTC
Animal Health
Generics
and
Biosimilars
Innovative
Medicines
20 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
Novartis Position on Biosimilars – Principles 1-4
| Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only 21
Biosimilars are
biologics
Biosimilars should be subject to the same requirements as any
other biologics of the same class
Interchangeability A biosimilar that has been registered via a robust regulatory
pathway has demonstrated to have the same clinical profile
as the reference product
Step-wise
development
of biosimilars
Biosimilar development programs should follow step-wise approach
and be scientifically sound
Extrapolation of
indication possible
Extrapolation of indication should be allowed if scientifically
justified, i.e. if „totality-of-evidence‟ has been demonstrated
For details please refer to: http://www.novartis.com/downloads/corporate-responsibility/resources/positions/biosimilars-science-based-
approval-sustainable-market-access.pdf
Novartis Position on Biosimilars – Principles 5-8
| Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only 22
Same INN for
biosimilars
Biosimilar and reference product should have the same INN if the
molecular characteristics of the biosimilar are within the reference
product‟s range of variability and comparable safety and efficacy
have been shown
Fair competition
in the market
Novartis supports both, the promotion of innovation and the
possibility of fair competition by biosimilar products following
loss of exclusivity
Same pharmaco-
vigilance for
biosimilars
Robust and adequate pharmacovigilance measures needed for all
medicinal products based on their individual risk profile
High registration
standards
for biosimilars
Local approval requirements need to ensure high standards of
comparability between reference and biosimilar products
For details please refer to: http://www.novartis.com/downloads/corporate-responsibility/resources/positions/biosimilars-science-based-
approval-sustainable-market-access.pdf
Table of Contents
Key Principles of Biosimilar development
• What is a Biosimiliar?
• Differences to Generic Medicines
• Development via a Two-Step Procedure
Overview of international Guidance on Biosimilars
Novartis Position on Biosimilars
Summary and Regulatory Needs
23 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
Summary – Biosimilars...
... are successors to a biologic medicine that has been marketed based on a full registration dossier and has lost its exclusivity
... are not simple generics due to their complexity in terms of size, structure and manufacturing and therefore require a specific registration pathway
... have demonstrated similarity to the reference product via a two-step comparability procedure:
a. Analytical investigation to demonstrate structural and functional similarity
b. Targeted non-clinical and clinical trials to confirm similarity - de novo proof of efficacy not necessary
| Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only 24
Biosimilars should be approved according to specific, highly stringent regulations
High-quality biosimilars are safe treatment options and have the same issues as all other biologics, but do not generate more concerns
The quality standards for biosimilars should be the same as for original biologics
Biosimilars should be evaluated according to rigorous guidelines1, and must have
• Highly comparable structural and functional attributes
• No clinically relevant differences
Products that do not meet these high standards for similar biological products should not be approved and not put in circulation
A robust pharmacovigilance system should be in place to support patient safety with all medicinal products
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1 Refer to guidance from WHO, EMA and/or FDA
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