19. Agnes Klein - Health Canada


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Wednesday, 20 November, 2013
Latin America Biotherapeutic Conference Day 2

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19. Agnes Klein - Health Canada

  1. 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. 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 2
  3. 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) 3
  4. 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 . 4
  5. 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 5
  6. 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 6
  7. 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 7
  8. 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) 8
  9. 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 9
  10. 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 …”. 10
  11. 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” 11
  12. 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 12
  13. 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. 13
  14. 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. 14
  15. 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.” 15
  16. 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 16
  17. 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