Biosimilars are complex biologic drugs that are similar but not identical to innovative biologic reference products. Several key points are made: - Biosimilars are regulated differently than small molecule generics due to biologics' larger size and more complex manufacturing processes. - While some regulators may designate a biosimilar as interchangeable, decisions on substitution are made separately at a national or state level. - Health Canada does not declare any drug interchangeable and leaves substitution decisions to provinces, whereas the FDA may designate a biosimilar interchangeable if it is biosimilar and switching poses no greater risk to patients. - Automatic substitution is not recommended and interchangeability requires specifically designed clinical trials for each

1. gust 22, 2007
Draft
Helping the people
of Canada maintain and
improve their health
Aider les Canadiens et
les Canadiennes à maintenir
et à améliorer leur santé
Diversity of Approaches to the Interchangeability
and Substitutability of Biosimilars
Agnes V Klein, MD DPH
Jian Wang, MD PhD
Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics
Biologics and Genetic Therapies Directorate
Health Canada
November, 2013

2. Health Products and Food Branch
Highlights
What are the differences?
 Biologics vs pharmaceuticals
 Biosimilars vs generics
 Interchangeability for biosimilars
 A diversity of approaches to interchangeability
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3. Health Products and Food Branch
Biologics, unlike pharmaceuticals, are derived from a variety of expression
systems (e.g. human, animal, microorganism, cell culture) or produced using
recombinant DNA technology.
Examples of biological products: hormones, blood products, cytokines, growth factors,
vaccines, gene/cellular therapies, fusion proteins, monoclonal antibodies, etc.
Sensipar ® (chemical drug)
molecular size (weight = 393)
Enbrel ® (protein drug)
molecular size (weight = 150,000)
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4. Health Products and Food Branch
Pharmaceuticals vs Biologics
Pharmaceuticals
Biologics
Method of synthesis
Chemical
Living organism or cells
Molecular Size
Small
Large
Structure
Usually fully known
Complex, frequently
partially unknown
Susceptibility to
contamination during
manufacturing
Low
High
Sensitivity to physical
factors (e.g., heat, light)
Low
Higher
Manufacturing methods
Relatively simple
Complex
.
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5. Health Products and Food Branch
Biologics vs Pharmaceuticals
Biologics
Pharmaceuticals
Molecular weight
Large
Small
Species*
Specific
Independent
Immunogenicity*
Antigenic (MW>10kDa)
Non antigenic (generally)
absorption*
Slower (s.c., i.m.)
Faster
distribution
Low/Limited
High
metabolism
Catabolized to endogenous
amino acids
Metabolized to non-active and
active metabolites
disposition*
Often target-mediated
Rarely target-mediated
PK profile*
Non-linear (often)
Linear (frequently)
Half-life
Long
Short(er)
Safety
Exaggerated pharmacology
Toxicity (variable
mechanisms)
ADME
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6. Health Products and Food Branch
Regulatory Pathways for Biosimilars
• It is widely accepted by global regulatory agencies and the biotech
industry that biosimilars cannot be identical copies of the innovator
products
• Inherent differences require different regulatory considerations and
guidelines tailored to biosimilars
• Many countries as well as WHO have published guidance documents on
how to regulate biosimilars
• In Canada, biosimilars are regulated as New Drugs by comparison with a
reference product previously authorized and marketed in Canada
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7. Health Products and Food Branch
Biosimilars vs Generics
Biosimilars
Generics
Regulatory Pathway
NDS
ANDS
Drug Substance
Similar to reference
Identical to reference
(Pharmaceutical
equivalence)
Comparative non-Clinical
Required
Not required
Comparative PK/PD
Similar PK/PD profile
Pharmacokinetic (PK)
equivalence (formal
declaration)
Comparative Clinical Trial
At least one
Not required
Efficacy/Safety
No meaningful difference
Therapeutic equivalence
Indication extrapolation
Case by case
Automatic
Interchangeability
Generally no
Yes
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8. Health Products and Food Branch
Post-market traceability: Biosimilars Made by Many
Companies
Sandoz, the generic drug division of Swiss
drug giant Novartis AG, is determined to
lead the biosimilar field
Amgen Inc, the world's largest
biotechnology company, and generic
drugmaker Watson Pharmaceuticals Inc
will work together to develop and sell
biosimilar versions of several biotech
cancer drugs
Pfizer, the world‟s biggest pharmaceutical
firm, will work with Biocon, India‟s largest
biotech company, to bring “biosimilar”
insulin treatments to market
Merck & Co is to develop its own version of
Pfizer‟s ageing arthritis drug Enbrel with a
South Korean manufacturer, Hanwha
Korean electronics giant Samsung had
entered into a biosimilars joint venture with
US biotechnology company Biogen Idec
Apotex Inc., the largest Canadian-owned
generic pharmaceutical company and Intas
Biopharmaceuticals Limited of India have
extended their business agreement to
develop a biosimilar version of
pegfilgrastim (PegG-CSF)
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9. Health Products and Food Branch
Interchangeability declaration by HC
• Regulations: Health Canada doesn‟t declare interchangeability neither for
generics nor for biosimilars (Called Subsequent Entry Biologics, SEBs in
Canada))
• Health care: Interchangeability remains a provincial decision in Canada
• Clinical Practice: The decision to treat a patient with an originator‟s
product or a biosimilar is within the authority of a qualified healthcare
professional, and in the best interest of his/her patient/s
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10. Health Products and Food Branch
Health Canada’s Position re Interchageability
• In a 2010 letter to Provincial Drug Plans concerning its guidance
on the market autorisation of SEBs, Health Canada stated:
 SEBs are not “generic” biologics, and authorization of an SEB is not
a declaration of pharmaceutical or therapeutic equivalence to the
reference biologic drug.
 Reminding plans that, as a result of manufacturing drift, Health
Canada “… does not support automatic substitution of an SEB for its
reference drug …”.
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11. Health Products and Food Branch
Interchangeability vs. Substitutability (Canada)
• Not all regulators define the two terms ad distinct: in Canada, terms
are defined under various provincial laws, for example:
 “Interchangeability” generally refers to the requirement to “interchange” a
lower cost generic version of a name brand drug (a „cost-driven‟
decision)
(A condition for designation is that the drugs must be bioequivalent)
 “Substitutability” or “therapeutic substitution” generally refers to
substituting an altogether different drug as „functionally‟ equivalent to a
prescribed drug for treating the same condition (a medical decision)
• The situation is highly dependent on the specifics of the law, and
each province has different definitions of “interchangeability”
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12. Health Products and Food Branch
Therapeutic Interchangeability or Substitution
“Therapeutic interchangeability or substitution” could be supported by
specifically designed clinical trials for each indication, for example
Switch over
Biosimilar
Follow-up
Reference
Reference
Biosimilar
•Reference
Reference
Efficacy/Safety/
Immunogenicity
results
Reference
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13. Health Products and Food Branch
Interchangeability vs. Substitutability (Global)
In the EU, decisions
on the
interchangeability or
substitution of
biosimilars and
originator biologics
are not made by
EMA but at each
national level
(Fifteen nations
have prohibited
automatic
substitution)
While the FDA can
designate a
biosimilar as
interchangeable
with its reference
originator product ,
the individual states
govern the practice
of pharmacy
including drug
substitution laws
Health Canada
doesn‟t declare
interchangeability
neither for generics
nor for biosimilars.
Interchangeability
remains a provincial
decision in Canada.
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14. Health Products and Food Branch
Interchangeability under U.S. Legislation (FDA)
• Under U.S. legislation, Interchangeable or Interchangeability
means:
 The biological product is biosimilar to the reference product;
 It can be expected to product the same clinical result as the
reference product in any given patient; and
 For a biological product that is administered more than once to an
individual, the risk in terms of safety or diminished efficacy of
alternating or switching between use of the product and its
reference product is not greater than the risk of using the reference
product without such alternation or switch.
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15. Health Products and Food Branch
Interchangeability under U.S. Legislation (States)
• Some states are proposing or moving to vote on amendments to
their generic-equivalent laws to include guidance on biosimilars
• These amendments intend to establish that pharmacies can only
substitute if the FDA licenses a biosimilar as interchangeable and
then only if the physician does not specify “brand medically
necessary.”
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16. Health Products and Food Branch
Conclusions
• A Biosimilar is not identical to the reference biologic
• Each country has its own approach to interchangeability of
biosimilars based on the national or local law
• In contrast to a regulatory decision process on interchangeability,
substitution (or interchangeability) of biosimilars is an
administrative process (different in every country), which allows
pharmacies to substitute a prescribed product with another
“equivalent product”
• In many countries, automatic substitution of biosimillars is not
recommended
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17. Draft
Helping the people
of Canada maintain and
improve their health
Aider les Canadiens et
les Canadiennes à maintenir
et à améliorer leur santé
Thank you
Merci
agnes.v.klein@hc-sc.gc.ca
613-954-5706