“Biosimilars: Variable Approaches to Interchangeability and Substitutability” Explores discussions and concerns around the issue of interchangeability and illustrates the position of Health Canada

1. Helping the people
of Canada maintain and
improve their health
Aider les Canadiens et
les Canadiennes à maintenir
et à améliorer leur santé
Draft
Biosimilars: Variable Approaches to
Interchangeability and Substitutability
Jian Wang, MD PhD
Agnes V Klein, MD
Centre for Evaluation of Radiopharmaceuticals and Biotherapeutics
Biologics and Genetic Therapies Directorate
Health Canada
Moscow, May 15-16, 2013
•August 22, 2007

2. Health Products and Food Branch
Highlights
 Biologics are different from pharmaceuticals
 Biosimilars are not generics
 Health Canada does not declare interchangeability for biosimilars
 Global regulators have different approaches to interchangeability
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3. Health Products and Food Branch
Sensipar ® (chemical drug)
molecular size (weight = 393)
Enbrel ® (protein drug)
molecular size (weight = 150,000)
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.
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4. Health Products and Food Branch
Differences between Pharmaceuticals and 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
Differences between Biologics and Pharmaceuticals
Biologics Pharmaceuticals
Molecular weight Large Small
Species* Specific Independent
Immunogenicity* Antigenic (MW>10kDa) Non antigenic (generally)
ADME
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)
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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 and 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
7
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
Differences between Biosimilars and Generics

8. Health Products and Food Branch
Concerns with Automatic Substitution/ Interchaneability
• Quality: Two biologics can not be exactly the same. Minor differences in
the process used to produce biosimilars can lead to profound differences
in clinical activity and side effect profile that may not become apparent
until the product is in widespread use
• Safety: As a consequence of their complexity and impurity profile,
automatic interchangeability of biologics or biosimilars could give rise to
different (and sometimes unexpected) clinical consequences
• Immunogenicity: The immunogenicity of biosimilars cannot be fully
predicted using preclinical/clinical studies. Repeated switches between
the biosimilar(s) and originator‟s product may increase immunogenicity
with potentially negative effects
• Clinical: A biosimilar may not receive all indications or uses
• Lack of reliable post-market traceability: It is necessary for analyzing
the cause when an adverse drug reaction occurs (see next slide)
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9. 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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10. Health Products and Food Branch
No 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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11. Health Products and Food Branch
Health Canada’s Position towards Interchaneability
• In a 2010 letter to Provincial Drug Plans concerning its guidance
on approval of SEBs, Health Canada stated as follows:
 SEBs are not “generic” biologics, and authorization of an SEB is not
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 a SEB for its
reference drug …”.
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12. Health Products and Food Branch
Interchangeability vs. Substitutability (Canada)
• 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 of 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 provincial law
and each province has different definitions of “interchangeability”
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13. 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 Follow-up
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Efficacy/Safety/
Immunogenicity
results
Biosimilar
Reference
•ReferenceReference Reference
Reference
Biosimilar

14. Health Products and Food Branch
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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.
Interchangeability vs. Substitutability (Global)

15. 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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16. 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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17. 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 laws
• In many countries, automatic substitution of biosimillars is not
recommended
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18. Helping the people
of Canada maintain and
improve their health
Aider les Canadiens et
les Canadiennes à maintenir
et à améliorer leur santé
Draft
Thank you
Merci
спасибо
jian.wang@hc-sc.gc.ca
1-613-957-0833