9 Karin Heidenreich - Novartis

Biosimilars: Principles of their
Development and Evaluation
Dr. Karin Heidenreich / Global Public Policy R&D
Novartis International AG, Switzerland
Workshop on Biotherapeutics & Biosimilars
Lima/Peru on 19 November 2013

Disclaimer
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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.
2 | 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


Table of Contents




Different types of biologics in circulation
Not every version of a biologic is a biosimilar
Noncomparable

Counterfeit
medicine

Originator

Biosimilar

• First registration
of new molecule

• Version of
registered original
biologic

• Questionable copy
of registered original
biologic

• Illegal copy version
of registered
original biologic

• Approval based on
extensive
comparability
exercise via special
and stringent
registration pathway
(e.g. in EU)

• Approval not based
on demonstrated
comparability
without special
registration pathway;
sometimes standalone application

• Biological and
pharmaceutical
quality unclear,
mostly substandard
or even harmful

• Patients can expect
same clinical profile
as with originator

• Patients cannot
expect the same
clinical profile as
with originator

• Approval based
on demonstrated
quality, safety
and efficacy


Different types of biologics in circulation
Not every version of a biologic is a biosimilar
Noncomparable

Counterfeit
medicine

Originator

Biosimilar

• First registration
of new molecule

• Version of
registered original
biologic

• Questionable copy
of registered original
biologic

• Illegal copy version
of registered
original biologic

• Approval based on
extensive
comparability
exercise via special
and stringent
(e.g. in EU, USA,
Canada, Australia)

• Approval not based
on demonstrated
comparability
without special
registration pathway;
sometimes standalone application

• Biological and
pharmaceutical
quality unclear,
mostly substandard
or even harmful

• Approval based
on demonstrated
quality, safety
and efficacy

• Patients can expect
same clinical profile
as with originator

• Patients cannot
expect the same
clinical profile as
with originator


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.
1 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500142978.pdf


Differences between Generics and Biosimilars
Small
molecules

Expiry of patent and
other exclusivities

Biosimilars

Generics
 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

Original
biologics

 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


Development of high-quality biosimilars is a systematic
and robust process with two key steps
Step 1

Step 2

Develop highly similar product

Drug substance
Formulation / Drug product

Technical development to achieve a
“highly similar” molecule, which
matches the quality attributes of the
reference product
Demonstration of structural and
functional similarity

Confirm biosimilarity

GLP Tox.

Phase I

Phase III

Process validation

Targeted non-clinical and clinical
program to demonstrate similarity
Scope depends on similarity in quality
attributes and requires agreement
with health authorities


Step 1: Variability of the reference product defines
the target
Biological Activity (Units/mg)

Biologic products vary from batch
to batch
• 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

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

Batch of drug substance (DS)

Schneider, C. K.: Biosimilarity: A better definition of terms and
concepts. 25th Annual DIA EuroMeeting, 04-06/03/2013, Amsterdam

140

ADCC Potency
[% of reference]

2,0

Unfucosylated G0
[% of glycans]

PostShift

1,6

120

PostShift

100

80

12.2008

0,8

Pre-Shift

0,4

Pre-Shift
60
08.2007

1,2

05.2010

Expiry Date

09.2011

0,0
08.2007

12.2008

05.2010

09.2011

Expiry Date

Schiestl, M., et al.: Acceptable Changes in Quality Attributes of Glycosylated
Biopharmaceuticals. Nature Biotechnology, 29 (4): 310-312, 2011


Biosimilars are approved biologics with
comparable Q, S and E to a reference product
Approved biosimilar in EU

What is a biosimilar?

NO difference to originator

• Developed and manufactured using state-of-theart technology
• Demonstrated comparable quality (Q), safety (S),
and efficacy (E) to a reference product
• Approved via stringent regulatory pathways

Sample

1

2

3

4

Brockmeyer C & Seidl A et al. Eur J Hosp Pharm
Pract 2009;15:34–40

What is NOT a biosimilar?

Non-comparable “copy biologic” ≠ biosimilar

• Non-comparable or alternative copy biologics are
NOT biosimilars

NOT similar to Reference E

• Have not demonstrated biosimilarity via a stateof-the-art comparability exercise
• Not approved following a specific biosimilars
registration pathway (e.g. in line with WHO
recommendations)

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

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


Illustration of the difference between originator
and biosimilar development
Originator
development

Biosimilar
development
Additional clinical studies

Clinical
studies
PK/PD
Non-clinical

The world
turned upside
down....

Analytical

PK/PD
Non-clinical

Analytical

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

Source: modified slide shown by EGA at EMA Workshop in London on 31 Oct 2013

Table of Contents




WHO – 2009 Guidelines on evaluation of similar
biotherapeutic products (SBPs)
 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.”
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

European Medicines Agency
EU Guidelines for Biosimilars
General
General Biosimilar
Brochure

Product-specific

Other

Somatropin

Statistical methods
for comparability in
quality attributes*

Epoetin

Q&A Document

“Overarching”

G-CSF

Insulin
LMWH

Quality

Interferon alfa

Non-clinical

Risk Management
Plan

Interferon beta

Clinical

Immunogenicity
assessment of
biotech products

Monoclonal
Antibodies
Follicle Stimulation
Hormone

G-CSF: Granulocyte-colony stimulating factor (filgrastim or lenograstim); LMWH: Low Molecular Weight Heparin; *Concept paper

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‟
1 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologic
Applications/Biosimilars/

Table of Contents




Novartis develops both, innovative medicines
and biosimilars of high quality
Environment

Patient needs

Novartis portfolio
Pharmaceuticals

Innovative
Medicines

Innovative
medicines
Alcon
(Eye care)

Sandoz

Prevention

(Generics)

Full range
of healthcare
options

OTC

Affordable
options

Animal Health
Self-care

Vaccines and
Diagnostics


Generics
and
Biosimilars

Novartis Position on Biosimilars – Principles 1-4
Biosimilars are
biologics

Step-wise
development
of biosimilars

Biosimilars should be subject to the same requirements as any
other biologics of the same class

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

Interchangeability

A biosimilar that has been registered via a robust regulatory
pathway has demonstrated to have the same clinical profile
as the reference product

For details please refer to: http://www.novartis.com/downloads/corporate-responsibility/resources/positions/biosimilars-science-basedapproval-sustainable-market-access.pdf

Novartis Position on Biosimilars – Principles 5-8
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

Same pharmacovigilance 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

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

For details please refer to: http://www.novartis.com/downloads/corporate-responsibility/resources/positions/biosimilars-science-basedapproval-sustainable-market-access.pdf

Table of Contents




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

 ... have demonstrated similarity to the reference product via a twostep 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


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
1 Refer to guidance from WHO, EMA and/or FDA

9 Karin Heidenreich - Novartis

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