28. Dr. Jiang Wang - Health Canada


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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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28. Dr. Jiang Wang - Health Canada

  1. 1. Helping the peopleof Canada maintain andimprove their healthAider les Canadiens etles Canadiennes à mainteniret à améliorer leur santéDraftBiosimilars: Variable Approaches toInterchangeability and SubstitutabilityJian Wang, MD PhDAgnes V Klein, MDCentre for Evaluation of Radiopharmaceuticals and BiotherapeuticsBiologics and Genetic Therapies DirectorateHealth CanadaMoscow, May 15-16, 2013•August 22, 2007
  2. 2. Health Products and Food BranchHighlights Biologics are different from pharmaceuticals Biosimilars are not generics Health Canada does not declare interchangeability for biosimilars Global regulators have different approaches to interchangeability2
  3. 3. Health Products and Food BranchSensipar ® (chemical drug)molecular size (weight = 393)Enbrel ® (protein drug)molecular size (weight = 150,000)Biologics, unlike pharmaceuticals, are derived from a variety of expressionsystems (e.g. human, animal, microorganism, cell culture) or produced usingrecombinant DNA technology.Examples of biological products: hormones, blood products, cytokines, growth factors,vaccines, gene/cellular therapies, fusion proteins, monoclonal antibodies, etc.3
  4. 4. Health Products and Food BranchDifferences between Pharmaceuticals and BiologicsPharmaceuticals BiologicsMethod of synthesis Chemical Living organism or cellsMolecular Size Small LargeStructure Usually fully knownComplex, frequentlypartially unknownSusceptibility tocontamination duringmanufacturingLow HighSensitivity to physicalfactors (e.g., heat, light)Low HigherManufacturing methods Relatively simple Complex4.
  5. 5. Health Products and Food BranchDifferences between Biologics and PharmaceuticalsBiologics PharmaceuticalsMolecular weight Large SmallSpecies* Specific IndependentImmunogenicity* Antigenic (MW>10kDa) Non antigenic (generally)ADMEabsorption* Slower (S.C., I.M.) Fasterdistribution Low/Limited Highmetabolism Catabolized to endogenousamino acidsMetabolized to non-active andactive metabolitesdisposition* Often target-mediated Rarely target-mediatedPK profile* Non-linear (often) Linear (frequently)Half-life Long Short(er)Safety Exaggerated pharmacology Toxicity (variablemechanisms)5
  6. 6. Health Products and Food BranchRegulatory Pathways for Biosimilars• It is widely accepted by global regulatory agencies and the biotechindustry that biosimilars cannot be identical copies of the innovatorproducts• Inherent differences require different regulatory considerations andguidelines tailored to biosimilars• Many countries and WHO have published guidance documents on howto regulate biosimilars• In Canada, biosimilars are regulated as New Drugs by comparison with areference product previously authorized and marketed in Canada6
  7. 7. Health Products and Food Branch7Biosimilars GenericsRegulatory Pathway NDS ANDSDrug Substance Similar to reference Identical to reference(Pharmaceuticalequivalence)Comparative non-Clinical Required Not requiredComparative PK/PD Similar PK/PD profile Pharmacokinetic (PK)equivalence (formaldeclaration)Comparative Clinical Trial At least one Not requiredEfficacy/Safety No meaningful difference Therapeutic equivalenceIndication extrapolation Case by case AutomaticInterchangeability Generally no YesDifferences between Biosimilars and Generics
  8. 8. Health Products and Food BranchConcerns with Automatic Substitution/ Interchaneability• Quality: Two biologics can not be exactly the same. Minor differences inthe process used to produce biosimilars can lead to profound differencesin clinical activity and side effect profile that may not become apparentuntil 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 todifferent (and sometimes unexpected) clinical consequences• Immunogenicity: The immunogenicity of biosimilars cannot be fullypredicted using preclinical/clinical studies. Repeated switches betweenthe biosimilar(s) and originator‟s product may increase immunogenicitywith potentially negative effects• Clinical: A biosimilar may not receive all indications or uses• Lack of reliable post-market traceability: It is necessary for analyzingthe cause when an adverse drug reaction occurs (see next slide)8
  9. 9. Health Products and Food BranchPost-market traceability: Biosimilars Made by ManyCompaniesSandoz, the generic drug division of Swissdrug giant Novartis AG, is determined tolead the biosimilar fieldAmgen Inc, the worlds largestbiotechnology company, and genericdrugmaker Watson Pharmaceuticals Incwill work together to develop and sellbiosimilar versions of several biotechcancer drugsPfizer, the world‟s biggest pharmaceuticalfirm, will work with Biocon, India‟s largestbiotech company, to bring “biosimilar”insulin treatments to marketMerck & Co is to develop its own version ofPfizer‟s ageing arthritis drug Enbrel with aSouth Korean manufacturer, HanwhaKorean electronics giant Samsung hadentered into a biosimilars joint venture withUS biotechnology company Biogen IdecApotex Inc., the largest Canadian-ownedgeneric pharmaceutical company and IntasBiopharmaceuticals Limited of India haveextended their business agreement todevelop a biosimilar version ofpegfilgrastim (PegG-CSF)9
  10. 10. Health Products and Food BranchNo Interchangeability declaration by HC• Regulations: Health Canada doesn‟t declare interchangeability neither forgenerics nor for biosimilars (Called Subsequent Entry Biologics, SEBs inCanada))• Health care: Interchangeability remains a provincial decision in Canada• Clinical Practice: The decision to treat a patient with an originator‟sproduct or a biosimilar is within the authority of a qualified healthcareprofessional, and in the best interest of his/her patient(s)10
  11. 11. Health Products and Food BranchHealth Canada’s Position towards Interchaneability• In a 2010 letter to Provincial Drug Plans concerning its guidanceon approval of SEBs, Health Canada stated as follows: SEBs are not “generic” biologics, and authorization of an SEB is notdeclaration of pharmaceutical or therapeutic equivalence to thereference biologic drug. Reminding plans that, as a result of manufacturing drift, HealthCanada “… does not support automatic substitution of a SEB for itsreference drug …”.11
  12. 12. Health Products and Food BranchInterchangeability vs. Substitutability (Canada)• In Canada, terms are defined under various provincial laws, forexample, “Interchangeability” generally refers to the requirement to “interchange” alower 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 tosubstituting an altogether different drug as „functionally‟ equivalent to aprescribed drug for treating the same condition (a medical decision)• The situation is highly dependent on the specifics of provincial lawand each province has different definitions of “interchangeability”12
  13. 13. Health Products and Food BranchTherapeutic Interchangeability or Substitution“Therapeutic interchangeability or substitution” could be supported byspecifically designed clinical trials for each indication, for exampleSwitch over Follow-up13Efficacy/Safety/ImmunogenicityresultsBiosimilarReference•ReferenceReference ReferenceReferenceBiosimilar
  14. 14. Health Products and Food Branch14In the EU, decisionson theinterchangeability orsubstitution ofbiosimilars andoriginator biologicsare not made byEMA but at eachnational level(Fifteen nationshave prohibitedautomaticsubstitution)While the FDA candesignate abiosimilar asinterchangeablewith its referenceoriginator product ,the individual statesgovern the practiceof pharmacyincluding drugsubstitution lawsHealth Canadadoesn‟t declareinterchangeabilityneither for genericsnor for biosimilars.Interchangeabilityremains a provincialdecision in Canada.Interchangeability vs. Substitutability (Global)
  15. 15. Health Products and Food BranchInterchangeability under U.S. Legislation (FDA)• Under U.S. legislation, Interchangeable or Interchangeabilitymeans: The biological product is biosimilar to the reference product; It can be expected to product the same clinical result as thereference product in any given patient; and For a biological product that is administered more than once to anindividual, the risk in terms of safety or diminished efficacy ofalternating or switching between use of the product and itsreference product is not greater than the risk of using the referenceproduct without such alternation or switch.15
  16. 16. Health Products and Food BranchInterchangeability under U.S. Legislation (States)• Some states are proposing or moving to vote on amendments totheir generic-equivalent laws to include guidance on biosimilars• These amendments intend to establish that pharmacies can onlysubstitute if the FDA licenses a biosimilar as interchangeable andthen only if the physician does not specify “brand medicallynecessary.”16
  17. 17. Health Products and Food BranchConclusions• A Biosimilar is not identical to the reference biologic• Each country has its own approach to interchangeability ofbiosimilars based on the national or local laws• In many countries, automatic substitution of biosimillars is notrecommended17
  18. 18. Helping the peopleof Canada maintain andimprove their healthAider les Canadiens etles Canadiennes à mainteniret à améliorer leur santéDraftThank youMerciспасибоjian.wang@hc-sc.gc.ca1-613-957-0833