5 Biologic versus “Small Molecule” Sensipar ® (chemical drug) Small molecular size(weight = 393)Larger molecular size and weight than “small molecules” (traditional pharmaceuticals)Derived from living organismsEach cell line is uniqueDifficult to produce and replicateEnbrel ® (protein) Immense molecular size(weight = 150,000)
6 What is an SEB / Biosimilar? An SEB is biologic drug that enters the market subsequent to a version previously authorized in Canada, and with demonstrated similarity to a reference biologic drug.Amgen Corporate Template6
7 When is “The Same” Not the Same? Images of EPO alfa purported to be “the same”, made throughout the world.
8 Typical Protein Production Process Different manufacturers will have different processes Will result in different biophysical characteristicsDifferent downstream processingSTARTENDProbably same gene sequenceTypical Protein Production ProcessDifferent fermentation/culture conditionsDifferent vectorDifferent host cell
9 Unwanted Immunogenicity PatientsProteinsInduce antibodiesNo effectNeutralise biologicaleffects and compromisefurther therapye.g., Factor VIII, GM-CSFCross-react with nativeprotein and induce adversereactionse.g., EPOAlterPharmaco-kinetics
10 What’s In A Name? Follow-on Protein Products (FOPP) Follow-on Biologics (FOB)Subsequent Entry Biologics (SEB)BiosimilarsSimilar Biotherapeutic Products (SBP)
12 Biosimilars/SEBs have been in Europe for the past few years LegislativeRegulatoryFrameworkCommercial200220032004200520062007200820092010201120122013LegislativeRegulatoryFrameworkCommercialRegulatoryFrameworkLegislative?Commercial
13 European Medicines Agency scientific guidelines for biosimilars1 TITLE MAIN MESSAGESGuideline on Similar Biological Medicinal ProductsGeneric standards do not applySimilar, but not identicalJustify any differencesGreater differences require more clinical dataGuideline on Similar Biological Medicinal ProductsContaining Biotechnology-Derived Proteins as ActiveSubstance: Quality IssuesEquivalent efficacySimilar safety (not worse)Similar immunogenic potentialGuideline on Similar Biological Medicinal ProductsContaining Biotechnology-Derived Proteins as ActiveSubstance: Nonclinical & Clinical IssuesActual non-clinical and clinical requirementsStudy designs, post-marketing commitments etc.Recombinant Human ErythropoietinRecombinant Human G-CSFRecombinant Human InsulinRecombinant Human Growth Hormone1
17 Clinical Testing is needed to determine efficacy and patient safety Omnitrope (somatropin)2Reference product: Genotropin (Pfizer)Alpheon (interferon alfa-2a)3Reference product: Roferon-A (Roche)57% of patients developed antibodies to Omnitrope in the first studyProblem was residual host-cell proteinRe-developed purification processConducted a second phase 3 studyAntibody levels reducedLower qualityNot as pure as Roferon-ALower efficacy than Roferon-AMore patients relapsedSafety profile worse than Roferon-AMore side-effectsEuropean Medicines Agency ReviewEuropean Medicines Agency ReviewAPPROVEDREJECTEDPractical experience from Europe informs the SEB discussion elsewhere2.3.
18 Substitution EU states are preventing automatic substitution Substitution by pharmacist without physician consent has been rejected bymore than half of the EU member states – including France, Germany, UK, Italy and Spain
20 President Obama speech to American Medical Association – June 2009 On Health Care Reform:“…we need to introduce generic biologic drugs into the marketplace. These are drugs used to treat illnesses like anemia. But right now, there is no pathway at the FDA for approving generic versions of these drugs.”
21 US healthcare reform legislation passed March 2010 One aspect was a pathway for biosimilar approvalsSome requirements specified in text of legislation:Information showing same mechanism of action for proposed condition(s) of use (to the extent MOA is known for reference product)Information showing same dosage form, strength, and route of administrationNext, the FDA will determine how to bring this new pathway to implementation.21
23 Canada is unique in establishing a regulatory framework without new biosimilar-specific legislation or regulationsLegislativeRegulatoryFrameworkCommercial200220032004200520062007200820092010201120122013LegislativeRegulatoryFrameworkApril 22, 2009Health Canada approves the first biosimilar in Canada: Sandoz’ Omnitrope (somatropin)CommercialRegulatoryFrameworkLegislative?Commercial
24 Health Canada’s Development of a Regulatory Approval Pathway for SEBs “Fact Sheet” issuedDraft guidance issued for commentFace-to-Face Consultation2nd draft issued for commentFinal Guidance IssuedNumerous opportunities for dialogueWritten comments always welcomedOpen consultationStakeholder comments appear to be taken into considerationFinal guidance appears science-based, with attention to patient safetyClearly, application and implementation will be key
26 Considerations Moving Forward “It is noteworthy that once approved, an SEB, like any new drug, cannot be substituted or used interchangeably with the reference product used in the studies.”Health Canada letter to BIOTECanada, June 23, 20091234Reliable data for post-approval studiesUncertain clinical consequences of repeated switchingPhysician opinion orDifferent approved clinical useAccurate and Clear PharmacovigilancePost-approval studies are a fundamental basis of biosimilar approvalRepeated changes would confound dataTheoretical potential for systematic lowering of immune toleranceSubtle potency or safety differences may have clinical consequencesPhysicians may specifically choose one biologic over anotherDifferent biologics may have different labelse.g. EU Sandoz EPO has no sc use in renal anemia11 ESAs in EURepeated changes would confound long-term safety dataRepeated or undocumented changes could compromise traceabilityHow to ensure this is understood by ALL participants in the healthcare system?
27 Europe is Tackling the “Traceability” Challenge of ESAs after the Fact 199820012009Eprex® (epoetin alfa)NeoRecormon® (epoetin beta)Eprex® (epoetin alfa)NeoRecormon® (epoetin beta)Aranesp® (darbepoetin alfa)Eprex® (epoetin alfa)NeoRecormon® (epoetin beta)Aranesp® (darbepoetin alfa)Dynepo® (epoetin delta)Mircera® (peg-epoetin beta)Ratioepo® (epoetin theta)Biopoin® (epoetin theta)Binocrit® (epoetin alfa)Abseamed® (epoetin alfa)Epoetin alfa Hexal (epoetin alfa)Silapo® (epoetin zeta)Retacrit® (epoetin zeta)= Full MAA*= Biosimilar MAAThree levels of information are needed for biologics and biosimilars to allow health authorities and manufacturers to trace an event to its root cause:Drug classIndividual manufacturer’s product – distinct nameManufacturer’s lot numberCan our current systems in Canada manage this?* Marketing Authorization Application
28 A Possible Solution – Australian approach A distinct name was assigned – clearly differentiating from epoetin alfaThis would be highly useful to overcome pharmacovigilance challenges
29 Patient safety must always remain the highest priority In ConclusionThough some concerns remain, Canada’s SEB regulatory environment is evolving wellFurther considerations should includeeducation of stakeholders on criticality of knowing what was prescribed and what was dispenseddistinct naming (INNs)Our approach should be always be supported by sciencePatient safety must always remain the highest priority