Biosimilars:
Concepts Clinicians Should Know
Cecilia C. Maramba-Lazarte, MD, MSCID
What will be discussing in the next
few minutes?
• Definitions and synonyms
• Difference between generics and
biosimilars
• Regulatory pathway of biosimilars- EMEA
example
• Global, Philippines situation
References
• Locatelli F and Roger S. Comparative testing and
pharmacovigilance of biosimilars. Nephrol Dial Transplant
2006; (S5):v13-v16.
• Genazzani AA, Biggio G, et al. Biosimilar Drugs.
Biodrugs 2007; 21 (6): 351-356.
• Misra M, Biosimilars: Current perspectives and future
implications. Indian J Pharmacol 2012; 44: 12-14
• Slide set RM Sharma- Biosimilar Drugs
• Slide set Ajay Singh- What are the issues?
www.patientsorganizations.org/.../Biosimilars%20-.
• Slide set Klara Tiitso- Biosimilars in the European Union
www.old.health.gov.il/.../pages/Dr._Klara_Tiitso_EMA_-_
References
• CHMP-EMA. Guideline on Similar Biological Medicinal
Products, October 2005
• Dranitsaris G, Emir E, Dorward K. Biosimilar of Biologic
Drug Therapies. Drugs 2011; 71 (12): 1527-1536.
• Niederwieser D, Schmitz S. Biosimilar agents in
oncology/haematology: from approval to practice. Europ J
or Haematology 2010; 86:277-288.
• Kuhlmann M, Covic A. The protein science of
biosimilars. Nephrol Dial Transplant 2006; 21 (S5): v4-v8.
• Sashidhar KS. Biosimilars an emerging market in Europe
http://www.frost.com/sublib/display-market-insighttop.do?id=241715269
• Israel.pdf
Biologics
• any virus, therapeutic serum, toxin,
antitoxin or analogous product applicable
to the prevention, treatment or cure of
diseases or injuries of man
• a wide range of products such as
vaccines, blood and blood components,
somatic cells, gene therapy, tissues and
recombinant therapeutic proteins
DRUGS and MEDICINES
• (Philippines)- refers to any chemical
compound or biological substance, other
than food, used in the treatment,
prevention or diagnosis of disease in
humans or animals
• Includes biologicals, biosimilars
Biological medicinal products
• A medicine whose active substance is
made by or derived from a living organism
• Synonymous to :
biologic medicine
biotherapeutic products
biopharmaceutical drugs
biotherapeutics
therapeutic biologic product
BIOLOGICAL MEDICINAL PRODUCTS
• A medicine whose active substance is
made by or derived from a living organism
• Examples include
insulin, human growth hormone,
erythropoietin, granulocyte colony
stimulating factor, interferon alfa, and
monoclonal antibodies
Products receiving US FDA Approval
from 1993-2004
Biological Medicinal Products
• Typically replacing or supplementing a
natural protein produced by the body
• ≈120 existing agents
• >400 biological medicinal products in
development for cancers, infectious
diseases, and autoimmmune diseases
Off patent biological medicinal products may
be produced by other companies as
biosimilars
Biosimilars
• terms used to describe officially-approved
subsequent versions of
innovator biological medicinal products.
• similar rather than identical
• Synonymous to: subsequent entry
biologics (SEBs) in Canada
similar biologic therapeutic produts
(WHO)
Patent expiry for innovator biological
medicinal products in the EU
Global market size of biological medicinal
products with expiring patents
Drug
Global market size
(US$ bn, 2002)
Epoetins
8.4
Insulins
4.4
Interferon-
4.0
Colony-stimulating
factors
2.7
Interferon-
2.4
Growth hormones
1.7
Follicle-stimulating
hormones
0.8
Reuters Business Insight healthcare report, 2003.
Advantages of Biosimilars
• other companies may produce/distribute
off-patent drugs
• Ensures an adequate supply of
biopharmaceuticals at a lower cost
• Promotes competition
Biosimilars
SHOULD BE:
• Safe and efficacious
• Consistent in composition
• Stable when stored correctly
EMA states: “due to the complexity of
Biological/biotechnology derived products,
The generic approach is scientifically
not appropriate for these products”
Pharmaceuticals vs
Biological Medicinal Products
Molecular
weight
Pharmaceutical
Biological Medicinal
Products
0.05-1 kDa
5-200 kDa
Ex. Paclitaxel- 845 Da
G-CSF- 18,000 Da
Monoclonal Abs145,000-160,000 Da
Pharmaceuticals vs Biological
Medicinal Products
Pharmaceuticals
Manufacturing simpler
process
Biological Medicinal
Products
More complex
(a) Preparation
(b) Intermediates
(c) introduction
of functional groups
(c) coupling and
esterification
(d) separation processes (e)
purification
(a) Cloning of specific gene
(b) Transfer into host cell for
expansion
(c) Cell expansion
(d) Protein production
(e) Protein recovery
(f) Protein purification
(g) Formulationcharacterization and stability
Only chemical structure of
the drug needs to be
reproduces
Both protein structure and folds
need to be reproducedmolecular structure
determines function
bot
MANY OF THE PROCESSES ARE HIGHLY SENSITIVE
Pharmaceuticals vs Biological Medicinal
Products
Immunogenic reactions
Pharmaceuticals
Biological Medicinal
Products
Reaction are intrinsic to
the patient
Reactions may be
attributable to both
product and host-related
factors
Different products may
have different degrees of
immunogenicity
Variability in potency/ response and immunogenicity
may be due to differences in glycosylation, contamination
Or changes in 3D structure
Immunogenicity of Biologic medicinal
products and biosimilars
• Can be induced by active drug-substance
• May also be induced by impurities in
biological products, structural modifications
as a result of the manufacturing process
• May be induced by suboptimal storage
conditions
• Patient factors such as age, HLA expression,
co-morbid conditions and previous exposure
are also related to immunogenicity
• Route of administration may be factor
Biosimilars
• manufacturing processes are difficult to
replicate EXACTLY due to complexity and
precision
• Manufacturing processes of biological
medicinal products are trade secrets
• Biosimilar manufacturers do not have access
to molecular clone and original cell bank, nor
to exact fermentation and purification process
Biosimilars
• Biosimilars may have different origins
• May have same therapeutic effect
• May have different side effects and
toxicology- ex. thrombotic vascular events,
tumor growth potential
• Interchangeability with reference products
is a critical issue
• Automatic substitution also an issue
Current EMA Guidelines for the
Approval of Biosimilars
Criterion
Requirement for regulatory approval
Pre-clinical
studies
Comparative non-clinical and toxicology
studies (ex. 28 day toxicity for G-CSF and
epoietin
Pharmacodynamics
Similarity markers should be based on
clinical efficacy (ex. For G-CSF, ANC and
CD34 in human volunteers
Pharmacokinetics Single dose SC or IV in human volunteers
(AUC)
Clinical trials
At least one equivalence trial relative to the
reference product is required or a 3-arm
trial relative to reference product and
placebo
Current EMA Guidelines for the
Approval of Biosimilars
Criterion
Extrapolation to
other diseases
Drug safety
Immunogenicity
Post-approval
requirements
Requirement for regulatory approval
May be permitted, but usually case-bycase basis
Safety must be demonstrated in at least
one equivalence trial with reference
product as control
All clinical trials must include antibody
testing
Specific monitoring must be performed for
efficacy in the extrapolated indications.
Comprehensive pharmacovigilance
program is required
• European Medicines agency recognized
the distinct difference between small
molecule medicines and biologic medicinal
products
• EMA Guideline on Similar Biological
Medicinal Products came into effect in
October 2005
Biosimilars Approved in Europe
Biosimilar (manufacturer)
Reference Product
Date of Approval
Human growth hormone (2)
Omnitrope (Sandoz)
Valtropin (Biopartners)
Genotropin (Pfizer)
April 2006
April 2006
Epoietin (5)
Abseamed (Medica Arzneimittel
Putter)
Retacrit (Hospira)
Binocrit (Sandoz)
Epoietin alfa Hexal (Hexal Biotech)
Silapo (STADA Arzneimittel)
Eprex (Janssen-Cilag)
Granulocyte colony stimulating
factor (7)
Filgrastim Hexal (Hexal Biotech)
Biograstim (CT Arzneimittel)
Nivestim (Hospira)
Zarzio (Sandoz)
Ratiograstim and Filgrastim
Ratiopharm (Ratiopharm
Tevagrastim (Teva Pharma)
Neupogen (Amgen)
August 2007
December 2007
August 2007
August 2007
December 2007
February 2009
September 2008
June 2010
February 2009
September 2008
September 2008
China and India- approval pathways not comprehensive
Philippines
• Biosimilars are here
• No specific
regulatory pathway
for biosimilars
• Question if
substitution by
pharmacists be
allowed
Conclusions
• Biosimilar portfolios are growing
• Biosimilars are a welcome development to
the clinician and end-users to address
problem of high costs
• Protection of patients is of utmost concern
• Manufacturing of biosimilars must be
supported by stringent controls
• Regulatory agency plays a key role to
address this concern