Biosimilars Knowledge
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Copyright © 2013 Quintiles
Introduction to biological medicines
and biosimilars
• A biosimilar is an approved version of a biological medicine with an
identical primary amino acid sequence to the originator and developed with
the intention to be as close to the originator as possible
• Like biological medicines, biosimilars are complex protein molecules that are
produced by living organisms
• During the past 15 years, biological medicines have had a profound impact on
healthcare
> primarily in the areas of rheumatology and oncology
> as well as endocrinology, cardiology, dermatology, gastroenterology, and neurology
• Many of the world’s top-selling medicines are now biological medicines
• However, biological medicines are expensive (sometimes by several orders of
magnitude more than small-molecule chemical drugs), limiting patient access
• As many biological medicines come off patent globally, there is great interest
in the development of biosimilars, which are likely to be more affordable
2
The increasing rate of development
of biosimilars
It has been estimated that 31 different companies were developing biosimilar
monoclonal antibodies (as of March 2012), compared with 18 companies as of
Sept 2011 – an increase of 67% in a 6-month period.1
Biological medicines due to come off patent2,3
2010–2015
2016–2020
Post–2020
Patent expiries expected:
Patent expiries expected:
Patent expiries expected:
91
46
99
1. Barkalow F, Biosimilar monoclonal antibodies. In the pipeline: major players and strategies. Citeline.
2. Haag T (Lonza) and Krattiger C (GfK). The emergence of biosimilars—How are they different from generics
and what are the implications from marketing? EphMRA presentation. June 29, 2011.
3. http://articles.chicagotribune.com/2012-08-13/news/sns-rt-elan-spinofftysabril6e8jd71t-20120813_1_tysabrielan-patent-protection
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As of Sept 2013, 16 biosimilars have been
approved in the EU*
Biosimilar
Sponsor
Reference product
Date of approval
Medice Arzneimittel Pütter
(Germany)
Eprex (Janssen)
August 2007
CT Arzneimittel
Neupogen (Amgen)
September 2008
Sandoz (unit of Novartis)
Eprex (Janssen)
August 2007
Hexal Biotech
(owned by Novartis)
Eprex/Erypo (Janssen)
August 2007
Hexal Biotech
Neupogen (Amgen)
February 2009
Hospira Enterprises
Neupogen (Amgen)
June 2010
Sandoz
Genotropin (Pfizer)
April 2006
Ratiograstim (filgrastim; G-CSF)
Ratiopharm
(acquired by Teva)
Neupogen (Amgen)
September 2008
Filgrastim Ratiopharm (filgrastim; G-CSF)
Ratiopharm
(acquired by Teva)
Neupogen (Amgen)
September 2008
(withdrawn April 2011**)
Hospira
Eprex (Janssen)
December 2007
Stada
Eprex (Janssen)
December 2007
Teva Pharma Industries
Neupogen (Amgen)
September 2008
BioPartners Gmbh
Humatrope (Eli Lilly)
April 2006
Sandoz (unit of Novartis)
Neupogen (Amgen)
February 2009
Inflectra (infliximab)
Hospira
Remicade (Janssen)
10 September 2013
Remsima (infliximab)
Celltrion
Remicade (Janssen)
10 September 2013
Abseamed (epoetin alfa)
Biograstim (filgrastim; G-CSF)
Binocrit (epoetin alfa)
Epoetin alfa Hexal (epoetin alfa)
Filgrastim Hexal (filgrastim; G-CSF)
Nivestim (filgrastim; G-CSF)
Omnitrope (somatropin; human growth hormone)
Retacrit (epoetin zeta)
Silapo (epoetin zeta)
Tevagrastim (filgrastim; G-CSF)
Valtropin (somatropin; HGH)
Zarzio (filgrastim; G-CSF)
*Out of a total of 20 marketing authorization applications. **The marketing authorization for Filgrastim Ratiopharm
was voluntarily withdrawn in 2011 at the request of the marketing authorization holder.
Source:EMA biosimilar EPAR listing: Accessed October 2013.
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Biosimilars differ from small-molecule
generic drugs – manufacture
Small-molecule generic
Biosimilar
Low molecular weight and complexity
High molecular weight and complex 3-D structure
Chemical synthesis
Produced by living organisms
Manufacturing process easy to reverse-engineer
Manufacturing process cannot be replicated
Identical copy of active ingredient
Although required to contain the same
primary amino acid sequence, the biosimilar
is not identical to the originator, but rather
highly similar
Even if a biosimilar uses the same
human gene as its originator
Human
gene
It will differ in other parts
of the process
Transfer into
host cell
DNA
vector
Cloning into DNA
vector
Bacterial or mammalian
cell produces protein
Fermentation
Different process = different product
Formulation
Adapted from The Biosimilars Handbook, Barclays Capital, 11 Feb 2011
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Biosimilars are subjected to a more
rigorous clinical development process
than generics
Small
molecule
• Proof of quality and bioequivalence
• No substantial clinical data required
• Reference to originator’s data
Generics
Biological
medicine
• Different manufacturing processes
can and often do yield differences
in the end product
• After the quality of a biological medicine
is demonstrated, some non-clinical and
clinical studies are necessary
• Immunogenic response cannot be
predicted and therefore must be tested
Biosimilars
Source: J. Mascaro: Regulatory evaluation of therapeutic biological medicines, Aug 15, 2007
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The potential impact of biosimilars
Expected cost savings
• A survey conducted in the European Union in 2010 found cost savings in
24 member states where biosimilars were marketed alongside their
originators*
> There was sustained price discounting in all countries, although this did vary at the
country level
> Values range from a 5% discount for filgrastim in the UK to a 53% discount for the
same medicine in Denmark in 2009
> The availability of biosimilars of somatropin, epoetin alfa, and filgrastim in Europe
has led to price discounts relative to their respective originators ranging from 5–82%
> The table below describes the mean price discount of biosimilar versions of the
medicines listed relative to their originator products
Mean discount in 24 EU member states
2007
2008
2009
Somatropin
25.4%
25.9%
14.1%
Epoetin
32.1%
17.3%
17.0%
Filgrastim
‐‐‐
10.8%
35.0%
*Rovira J, Espín J, García L, and Olry de Labry A. The impact of biosimilars’ entry in the EU market. 2011.
http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_market_012011_en.pdf.
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Biosimilars can improve healthcare
• Biosimilars can enable previously restricted therapies to become part of the
accepted standard of care
• In the UK, patients have benefited from lower acquisition costs and
improvements in the practice of medicine after the approval of a filgrastim
biosimilar
• This has enabled the routine use of filgrastim (as a biosimilar) as a first-line
treatment for the first time
UK filgrastim volume growth percent change
vs. previous year
November
2008
biosimilar
approved
17
13
• Many physicians moved filgrastim back to
first-line cancer treatment because of lower
biosimilars cost
• G-CSF prevents hospital readmission owing
to infection
• Biosimilars are less expensive than originator
biologics
• Zarzio “patient support kits” expand patient
access:
– Patients self-administer at home
– Efficiency savings repatriated
-2
2007
-5
2008
2009
2010
Note: Zarzio® (filgrastim) is not marketed in the United States.
Adapted with permission from Macmillan Publishers Ltd: Clin Pharmacol Ther (McCamish M and Woollett G.
The state of the art in the development of biosimilars. 91(3):405–417), © 2012
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Biosimilars must undergo rigorous testing
• To establish biosimilarity, the sponsor must first show that the candidate is highly
similar to the reference originator at the analytical level. This can take multiple
iterations in early-stage development before clinical testing may begin
• The sponsor must also perform detailed analysis of the originator reference,
especially if the structure and biological function is inadequately defined
Clinical
trials
PK/PD
Non-clinical
Biological
characterization
Analytics
Physicochemical
characterization
Process
development
Adapted with permission from Macmillan Publishers Ltd: Clin Pharmacol Ther (McCamish M and Woollett G.
The state of the art in the development of biosimilars. 91(3):405–417), © 2012
9
Examples of copies of biological medicines
from largely unregulated markets may not
meet today’s rigorous standards
• In the past, copies of biological medicines have been produced in some
countries where a rigorous regulatory pathway had not been established for
biosimilars
• These are known as copy-biologics, alternative biologics or intended copies
of biological products
• They may not meet the current criteria defined by the FDA or EMA for
biosimilarity and would not be approved in most regulated markets at the
present time without additional testing
• As guidelines are established worldwide to standardize the testing of
biosimilars for comparability against an originator product, the development
of such products becomes less widespread*
*Barkalow F, Biosimilar monoclonal antibodies. In the pipeline: major players and strategies. Citeline.
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Why immunogenicity testing is essential
• To date, there have been no reports of an approved biosimilar being associated with
any unusual or unexpected adverse events, although at least two biosimilars that are
currently approved in the EU encountered unwanted antibody development during
pre-approval clinical studies
• For a somatropin biosimilar, non-neutralizing antibodies were triggered by increased levels
of HCPs
• For an epoetin biosimilar, neutralizing antibodies were triggered leading to premature termination
of the clinical trial
• Changes in manufacturing process, however, have been associated with problems with
immunogenicity even in novel biological medicines
• Immunogenicity testing is therefore an essential part of the biosimilar testing process
Increased incidence of pure red cell aplasia
with EPREX® (epoetin) SC
Related to leachables from changes in primary
packaging
Immunogenicity of GM-CSF
Non-immunogenic in immunosuppressed patients
Antibodies in non-immunosuppressed patients
Thrombopoietin immunogenicity
Tryptophan-eosinophilamyalgia syndrome
Pegylated rHuMGDF: highly immunogenic
persistent thrombocytopenia meant development
program was stopped
Production strain changed: purification modified.
Unrecognized impurity caused EMS (>1300 cases,
38 deaths)
Saenger, P. Current status of biosimilar growth hormone. Int J Pediatr Endocroinol 2009; 370329.
Bennett, CL et al. Pure red-cell aplasia and epoetin therapy. NEJM 2004;351:1403–8.
Mascaro J, presentation . Mexico, August 15, 2007
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Highly regulated markets ensure
safe biosimilar medicines
• Biosimilar quality is assured by rigorous testing requirements, which include
head-to-head analytical/non-clinical/clinical testing against the reference
originator. In addition, the regulatory authorities, such as the European
Medicines Agency (EMA) and US FDA, require robustness in manufacturing
process
• To date, there have been no reports of a biosimilar medicine in highly
regulated markets being associated with any unusual or unexpected adverse
events as compared to its originator
• In Europe, no unusual or unexpected clinical events have been observed with
biosimilars of somatropin, epoetin, or filgrastim
• In the USA, no unusual or unexpected adverse events have been seen with
products approved as follow-on biologics on the basis of abbreviated data
packages, including Omnitrope®
McCamish M and Woollett G. The state of the art in the development of biosimilars.
Clin Pharmacol Ther 2012;91(3):405–417.
12
Biosimilar regulations in EU and
USA: different stages of development
• The EU pioneered the development of
biosimilar regulations
• US overarching guidelines issued
Product Class
Monoclonal
antibodies –
non-clinical and
clinical issues
Product Class
Specific Guideline:
Erythropoietin
(revised)
EMEA Legislative
Pathway
2004
2005
EMEA Regulatory
Guidance [Overarching
Guideline] under
revision
Quality Guideline;
Non-Clinical and
Clinical Guideline
(under revision )
2006
2007
Product Class
Specific Guidelines:
Insulin, G-CSF,
Somatropin
2008
2009
Product Class
Specific Guidelines:
Low molecular
weight heparin,
recombinant
Interferon-alpha
2010
Draft revisions to
Product Class
Specific Guideline:
Insulin, low molecular
weight heparin
Product
Product Class
Immunogenicity Class
assessment of Follicle
stimulating
monoclonal
hormone,
antibodies
Interferonbeta
2011
Public Health
Service Act
amended to
allow the
approval of
biosimilars
2012
Draft revisions
to Overarching
Guideline;
Quality
Guideline;
Non-clinical
and Clinical
Guideline
2013
Overarching Draft
Guidelines on
biosimilars
Europe
US
http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958c
The BPCI Act appears in Title VII, subtitle A of the Patient Protection and Affordable Care Act, March 2010.
US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference
product. Draft Guidance. Feb 2012.
13
The definition of ‘biosimilarity’ in the
USA vs EU
• USA: a biosimilar is “highly similar to the reference product notwithstanding minor
differences in clinically inactive components” and “there are no clinically
meaningful differences between the biological product and the reference product
in terms of the safety, purity, and potency”
• EU: a similar biological or 'biosimilar' medicine is a biological medicine that is
similar to another biological medicine that has already been authorized for use
and it does not have any meaningful differences from the reference medicine in
terms of quality, safety, or efficacy
McCamish M and Woollett G. The state of the art in the development of biosimilars.
Clin Pharmacol Ther 2012;91(3):405–417.
Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity
to a reference product. Draft Guidance. Feb 2012. Article 8 of Directive 2001/83, as amended.
14
Requirements of clinical studies
in the USA and EU
• Once a Phase I study establishes that a biosimilar possesses comparable
pharmacokinetic and pharmacodynamic attributes in human subjects to the
reference biological medicine, a Phase III study of safety, efficacy, and
immunogenicity is usually initiated
• Phase III studies use the most sensitive, homogeneous patient population
and clinical endpoint to establish the similarity of the biosimilar to the
reference and to be able to detect product-related differences
• If the mechanism of action (MoA) for the reference medicine is known, the
biosimilar medicine is expected to have the same MoA for the prescribed
conditions based on labeling
• Uses for the biosimilar medicine in its labeling must “have been previously
approved for the reference product”
• The extent, duration and timing of studies for evaluation of immunogenicity
vary depending on a variety of factors including:
> the expected duration of product use, nature of product, known incidence and clinical
consequences of immune response for the reference product, results of analytical
comparability studies
Gravel P, Naik A, Le Cotonnec J-Y. Biosimilar rhG-CSFs: how similar are they? Targ Oncol 2012; 7(Suppl 1):S3–S16.
US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference
product. Draft Guidance. Feb 2012.
15
Requirements of clinical studies
in the USA and EU
• US FDA requires a comparative repeat dose toxicity study in a relevant
species (if available) that includes toxicokinetic measurements, systemic
exposure, local tolerance, and immunogenicity assessments. EMA suggests
a risk-based approach to animal studies, taking into consideration factors
such as residual uncertainty at the end of in vitro studies and availability of
sensitive species/models for in vivo animal studies
• Both EMA and FDA require a sufficient number of product batches to be
tested during physiochemical and functional comparative studies to capture
the inherent batch-to-batch variability in product characteristics. The
biosimilar is expected to exhibit variability similar to the reference medicine
Chance K. US Biosimilar Guidelines: Summary and Insights 2012. Regulatory Focus April 2012
Datamonitor; Pharmaceutical key trends 2011—Biosimilar market overview.
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The biosimilar approval pathways
across highly regulated markets are similar
Criteria
EU and Australia
USA
Japan
Biosimilar pathway
status
Pathway established
Pathway established
Pathway established
Clinical trials
Mandatory, but extent
negotiable
Mandatory, but extent negotiable
Phase I studies mandatory,
Phase III studies may be
abbreviated in some situations
Reference medicine
Both biosimilar and originator
must have the same MOA.
Reference must be marketed
in the EU/Australia although
EU guidelines indicate that
studies utilizing a foreign
reference could be acceptable
Both biosimilar and originator
must have the same MOA.
Reference must be marketed in
the USA although US guidelines
indicate that studies utilizing a
foreign reference could be
acceptable
Reference must be approved and
marketed in Japan
Formulation
Same strength and route of
administration, otherwise
further studies required
Same strength and route of
administration
Same strength and route of
administration
Post-marketing safety
surveillance
Mandatory along with risk
management plan
Tailored to the particular safety
and effectiveness concerns
associated with the reference
medicine, its drug class, clinical
use elsewhere, and the biosimilar
candidate itself
Plan must be created to trace
adverse events and a drug safety
report submitted
Datamonitor; Biosimilars global regulatory update, May 2012. Regulatory agency websites.
US Food and Drug Administration. Guidance for industry. Scientific considerations in
demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012.
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The biosimilar approval pathways
across highly regulated markets are similar
Criteria
EU
USA
Equivalence
margins
Not currently defined, but
it is expected that equivalence
margins will be pre-defined by the
sponsor along with a strong
scientific justification prior to
conduct of clinical trials
Not currently defined, but it is expected that equivalence margins will
be pre-defined by the sponsor along with a strong scientific justification
prior to conduct of clinical trials
Extrapolation to
other indications
Will be permitted providing the
mechanism of action is the same
as the reference; scientific
justifications for extrapolation
are required
Scientific justification for extrapolation required, even if the biosimilar
and reference have the same mechanism of action:
 Relevant target receptors for each indication
 Pattern of molecular signaling upon receptor binding
 Expression and location of target receptors
 Relevance of pharmacodynamic measures to mechanism of action
 Relevance of pharmacokinetic values in different patient populations
 Differences seen in toxicities for the various conditions of use
in the various patient populations (non-comparative data)
Interchangeability
Decision at country level
Yes, if assessed by FDA based on adequate clinical data. Substitution
decisions made at the state level
US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating
biosimilarity to a reference product. Draft Guidance. Feb 2012.
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Comparative biosimilar approval
pathways across the world
Criteria
Canada
South Korea
India
China
Biosimilar
pathway
status
Pathway established
Pathway
established
Pathway established (2012)
No pathway; copy biological
medicines approved as new
drugs
Clinical trials
Mandatory, but extent
negotiable
Phase I studies
mandatory, Phase
III studies may be
abbreviated in
some situations
Phase I and Phase III trials
mandatory
Mandatory: Phase I–III studies
for copy biological medicines
with a reference not marketed
in China. Phase III studies for
copy biological medicines
marketed in China
Reference
medicine
Reference should be
approved and
marketed in Canada,
unless a waiver is
approved
Reference should
be approved and
marketed in South
Korea
Reference should be
approved and marketed in
India, although some flexibility
is allowed if reference is not
marketed in India
Not defined
Interchangeability
Decision at province
and territory level
Not defined
Not defined
Not defined
Formulation
Same dosage, form,
and route of
administration
Dosage, form, and
strength must be
the same
Same strength and route of
administration
Not defined
Postmarketing
surveillance
Mandatory along with
risk management plan
and period safety
updates
Pharmacovigilance
plan must be
submitted
Pharmacovigilance plan must
be submitted
Not defined
Datamonitor; Biosimilars global regulatory update, May2012. Regulatory agency websites.
Department of Biotechnology. Guidelines on similar biologics: Regulatory requirements for marketing authorization in India, 2012.
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EMA and FDA have rigorous
standards for biosimilar applications
• Biosimilar quality is assured by the rigorous testing that is integral to the
development and manufacturing process required by regulatory authorities
such as the European Medicines Agency and US FDA
• Following 20 marketing applications, the EMA has approved 16 biosimilar
medicines*
• Thus far, in the absence of differences in biophysical properties between
biosimilars and their originators, no significant clinical variation has been
observed
• Examples of EMA-rejected or withdrawn biosimilar applications:
Generic/Reference/
Biosimilar
Significant
biophysical
differences
Significant clinical variation from reference
Interferon-alfa-2a/Roferon-A/Alpheon
Yes
Yes
Yes
Yes
Human insulin/Humulin/Insulin Human
Rapid Marvel, Insulin Human 30/70 Mix
Marvel, and Insulin Human Long Marvel
Insufficient data
No
Yes
No
PK
Efficacy
Tolerability
*Post-approval, the marketing authorization for Filgrastim Ratiopharm was voluntarily withdrawn in 2011 at the request of the marketing authorization
holder (Ratiopharm), so 15 biosimilars are currently available.
Ahmed I, Kaspar B, and Sharma, U. Biosimilars: Impact of biologic product life cycle and European experience
on the regulatory trajectory in the United States. Clin Ther 2012; 34(2):400–419.
McCamish M and Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol
Ther 2012;91(3):405–417.
20
Regulatory guidelines for biosimilar
approvals are developing at different paces
Country
Inception
Approval pathway
Argentina
Sept 2009
Australia
June 2006
Administracion Nacional de Medicamentos, Alimentos y Tecnologia (ANMAT) published biologics and
biosimilar approval guidance
Agrees to follow CHMP/437/04 Guideline on Similar Biological Medicinal Products
Brazil
Dec 2010
Resolution 55/2010 regulates all biologic products
Canada
Mar 2010
Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics
China
All biologics, original or copy-biologics undergo the same pathway
Colombia
License for Manufacturing Facilities of Biological Products
EU
Oct 2005
CHMP/437/04 Guideline on Similar Biological Medicinal Products
EU
Nov 2010
Guideline on similar biological medicinal products containing monoclonal antibodies
India
Feb 2012
201 Department of Biotechnology finalizes guidelines for nonclinical evaluation of similar biologics
(biosimilars)
Japan
Mar 2009
Guidance issued by Japan’s Ministry of Health, Labour and Welfare
Malaysia
July 2008
Guidance Document for Registration of Biosimilars in Malaysia
Mexico
June 2009
Article 222 of the General Health Law
Russia
Biosimilars are subject to the same regulations as generics
Saudi Arabia Dec 2010
Guidelines on Biosimilars version 1.1
Singapore
April 2010
Appendix 17 of the Guidance on Medicinal Product Registration in Singapore
South Korea
Sept 2010
Taiwan
Nov 2008
Turkey
August 2008
Guidelines on the Evaluation of Biosimilar Products
Review Criteria for Registration and Market Approval of Pharmaceuticals-Registration and Market
Approval of Biological Products
Instruction Manual on Biosimilar Medical Products. Adopted EMA guidance into law 2011
USA
March 2010
Venezuela
August 2000
Law. No. 111–148, The Approval Pathway For Biosimilar Biologic Products
SRPB-R Guidelines: application for Health registry of DNA recombinant products, monoclonal and
therapeutic antibodies
Datamonitor. Biosimilars global regulatory update, May2012. European Generic Medicines Association, 2010.
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www.BiosimilarsKnowledgeConnect.com
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