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“Biosimilars: Variable Approaches to Interchangeability and Substitutability” Explores discussions and concerns around the issue of interchangeability and illustrates the position of Health Canada
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Helping the people of Canada maintain and improve their health
Aider les Canadiens et les Canadiennes à mainteniret à améliorer leur santé
Draft
Biosimilars: Variable Approaches to Interchangeability and Substitutability
Jian Wang, MD PhDAgnes V Klein, MD
Centre for Evaluation of Radiopharmaceuticals and BiotherapeuticsBiologics and Genetic Therapies Directorate
Health Canada Moscow, May 15-16, 2013
•August 22,
2007•8:45-11:45•Bantin
g Theatre
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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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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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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.
Health Products and Food Branch
Differences between Biologics and PharmaceuticalsBiologics 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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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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Health Products and Food Branch
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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
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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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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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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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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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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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
• Reference Reference Reference
Reference
Biosimilar
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)
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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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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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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Helping the people of Canada maintain and improve their health
Aider les Canadiens et les Canadiennes à mainteniret à améliorer leur santé
Draft
Thank youMerci
спасибо
jian.wang@hc-sc.gc.ca1-613-957-0833
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