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30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
30. Dr. Jaap Venema - Abbvie
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30. Dr. Jaap Venema - Abbvie

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“Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars” …

“Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars”

Provides an overview of regulatory and medical considerations on the interchangeability of biotherapeutic medicines

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    • 1. Regulatory and MedicalAspects of Interchangeabilityof Biologicals and BiosimilarsJaap Venema, Ph.D.Senior Director Biotherapeutics,Global Medical AffairsBIOTHERAPEUTIC MEDICINES.Regulatory challenges and currentpractices. Approaches forharmonization.MOSCOW, 16 MAY 2013
    • 2. Biologicals and BiosimilarsInterchangeability & Substitution:DefinitionsRegulatory PerspectiveClinical PerspectiveSummary and Conclusions
    • 3. Molecular Complexity of BiologicalsMW: 144.2Formula: C8H16O2Regulatory and Medical Aspects of Interchangeability of Biologicals and BiosimilarsMW: 747.95Formula: C38H69NO13Clarithromycin (BIAXIN™)Valproic Acid (Depakote™)MW: 18,464.5Formula: C821H1331N233O238S5Human Erythropoietin (EPOGEN™)MW: 148,683.5Formula: C6,440H9,928N1,704O2,011S561IGTAntibody Structure3
    • 4. Antibody StructureMolecular Weight: 148,683.5 [g/mol]Molecular Formula: C6,440H9,928N1,704O2,011S56•Four light chain domains•Eight heavy chain domains•Four inter-chain disulfide bonds•Twelve intra-chain disulfide bondsRegulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 4
    • 5. Antibody GlycosylationMolecular Weight: 148,683.5 [g/mol]Molecular Formula: C6,440H9,928N1,704O2,011S56•N-Linked Oligosaccharide- Naturally occurring post-translationalmodification- Stabilizes CH2 domain- Important determinant of Fc effector function- Can alter pKNA2F/Gal 2GlcNAcGalManFucNeuAcGlcNAcGalManFucNeuAcRegulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 5
    • 6. Antibody HeterogeneityMolecular Weight: 148,683.5 [g/mol]Molecular Formula: C6,440H9,928N1,704O2,011S56• Primary Sequence Variants• N-terminal heterogeneity• Splice variants• Mutations and mistranslations•Chemical Variants• Met oxidation• Asn deamidation• Isomerization• Thioether formation• Free –SH• Scrambled disulfides• Pyroglutamate formation• Post-translational modifications• O-linked glycoforms• Glycation• C-terminal lysine cleavageRegulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars6
    • 7. Antibody StabilityMolecular Weight: 148,683.5 [g/mol]Molecular Formula: C6,440H9,928N1,704O2,011S56• Physical Stability• Aggregation• Fragmentation• High Concentration Stability• Thermodynamic Stability• Chemical Stability• Turbidity• ViscosityRegulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 7
    • 8. 6,440 Carbon Atoms Are a Lot to Track• Few intact antibody structureshave been solved• Rarely is detailed structuralinformation available to helpguide process development• Differences frequently occur ina subpopulation of moleculesfurther complicating analyticalstudiesMolecular Weight: 148,683.5 [g/mol] Molecular Formula: C6,440 H9,928N1,704 O2,011 S56 (Anti-canine lymphoma monoclonal antibody “MAb 231”)Regulatory and Medical Aspects of Interchangeability of Biologicals and BiosimilarsHarris LJ, Larson SB, Hasel KW, McPherson A. Biochemistry. 1997 Feb 18;36(7):1581-97.What is important functionally?What is important functionally?We don’t know unless identified and clinically tested!8
    • 9. Carbo-hydratesProtein Function Is Highly Dependent on FinalConfigurationModified from Access Excellence of the NationalHealth Museum (http://www.accessexcellence.org/)Amino AcidsAlpha HelixPleaded SheetPleaded SheetAlpha HelixProtein Science of Biosimilars. Nephrol Dial Transplant (2006)[Suppl 5]: v4-v8Protein’s Higher OrderStructure - Ideally the SamePost-Translational Modifications - Will be DifferentMechanism(s) of Action?PK/PD?Tissue Distribution?Efficacy?Safety?Immunogenicity?}9Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars
    • 10. Two Different Processes CreateTwo Non-identical Biologic ProductsTypical Protein ProductionProcessENDENDDifferent biophysicalDifferent biophysicalcharacteristics in final productcharacteristics in final productDifferentdownstreamprocessingSTARTSTARTBoth may useBoth may usethe same genethe same genesequencesequenceDifferent fermentation/culture conditions10Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars
    • 11. Knowledge of and Input in Biologic and Biosimilar ManufacturingRegulatory and Medical Aspects of Interchangeability of Biologicals and BiosimilarsInnovator: In Process Testing Data From Every Process StepCell Bank Bioreactor Harvest Chromatography1, 2, 3Virus Filter ConcentrationBottlingBiosimilar:FinalProductDataPurificationCell Culture Final Dosage FormFor comparability, the innovator has a rich testing database from every inprocess step of every batch, the biosimilar only has access to the finalproduct11
    • 12. Biosimilars: Similar But Not the Same• Biosimilars manufactured by different manufacturers will differ from theinnovative product and from each other• They are not generic biologics• They use a different process to develop the biosimilar product• The active ingredient of a biosimilar can at best only resemble that of theoriginal biologic• This is recognized in regulatory guidances by EMA1and FDA2Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars1, Guidance for Industry Scientific Considerations in Demonstrating Biosimilarity to a Reference Product http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm.2. Guideline on Similar Biological Medicinal Products Containing Biotechnology-derived Proteins as Active Substance: Quality Issues EMA/CHMP/BWP/49348/2005.12
    • 13. Biologicals and BiosimilarsInterchangeability & Substitution:DefinitionsRegulatory PerspectiveClinical PerspectiveSummary and Conclusions
    • 14. 14Interchangeability, Substitution and Switching• Interchangeability - Health Regulatory Authority Designation• Expected to produce the same clinical result as the reference product in anygiven patient• Repeated switching between biosimilar and reference product presents nogreater safety or efficacy risk than continued use of the reference product• Substitution – Pharmacist Action• When a pharmacist substitutes a certain prescribed product by anotherequivalent product• If without the prescribing physician’s permission or knowledge, it isconsidered “automatic” or “involuntary” substitution• Switching - Treating Physician Decision• When a prescribing physician changes medication14Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars
    • 15. Interchangeability and Substitution for Generics• For generics, pharmaceutical equivalence =therapeutic equivalence• Regulators designate the two asinterchangeable• Depending on local or institutional rules,pharmacists may be authorized or even requiredto substitute a generic for the original withoutinforming the prescribing physician (automaticsubstitution)15Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars
    • 16. • For biosimilars pharmaceutical equivalence ≠therapeutic equivalence• Therefore, granting biosimilar status by aregulator does not imply interchangeability, andtherefore automatic substitution is not allowed• Depending on the regulatory agency,interchangeability has to be shown by the BSsponsorInterchangeability and Substitution for Biosimilars16Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars
    • 17. US1FDA requirements to meetinterchangeabilitythreshold still unclear,automatic substitution ofinterchangeable drugs tobe determined at statelevel.US1FDA requirements to meetinterchangeabilitythreshold still unclear,automatic substitution ofinterchangeable drugs tobe determined at statelevel.Japan3Interchangeability andautomatic substitutionhighly discouragedJapan3Interchangeability andautomatic substitutionhighly discouragedEMA2Decision on automaticsubstitution left tomember states - nocountry has explicitlyauthorized itEMA2Decision on automaticsubstitution left tomember states - nocountry has explicitlyauthorized itBrazil4Developed guidelines forbiosimilars, but has not yetaddressed interchangeability orautomatic substitutionBrazil4Developed guidelines forbiosimilars, but has not yetaddressed interchangeability orautomatic substitutionAustralia5Not applying substitution atthis time, but may considerin the futureAustralia5Not applying substitution atthis time, but may considerin the future1: FDA Biosimilar Guidance Webinar, February 15, 2012; 2: EMA, Questions and Answers on biosimilar medicines; European Biopharmaceutical Enterprises (EBE) Survey on Biosimilars, May 2011; 3: MHLWGuideline for Ensuring Quality, Safety and Efficacy of Biosimilar Products, March 2009 ; 4: FDLI Update, July 2012; 5: Discussion paper on Similar Biological Medicinal Products (SBMPs), Australia PBS; 6: HealthCanada Interchangeability and Substitutability of Subsequent Entry Biologics, July 2010Interchangeability and Automatic Substitution WorldwideRegulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 17Canada6Health Canada does notsupport automaticsubstitution, but allowsprovinces to determineinterchangeabilityCanada6Health Canada does notsupport automaticsubstitution, but allowsprovinces to determineinterchangeability
    • 18. Following passage in 2009 of the Biologics Price Competition and InnovationAct (BPCIA), FDA allows automatic substitution of “interchangeable”biosimilarsUnder U.S. law, interchangeable means:--FDA Biosimilar Guidance Webinar, February 15, 2012Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 18US FDAFDA BiosimilarWebinar• the biological product is biosimilar to thereference product• it can be expected to produce the sameclinical result as the reference product inany given patient• for a product administered more thanonce, the safety and reduced efficacyrisks of alternating or switching are notgreater than with repeated use of thereference product without alternating orswitching
    • 19. Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 19EU EMAThe EMA’s evaluations do not include recommendations on whether abiosimilar should be used interchangeably with its reference medicine:• the MA dossier does not contain evidence to substantiate an interchangeabilitydetermination, thus;• the granting of an MA for a biosimilar does not imply that the biosimilar isinterchangeable or substitutable with its reference (or other biologics)• “For questions related to switching from one biological medicine to another,patients should speak to their doctor and pharmacist.”However, the legal decision on interchangeability is left to memberstates--EMA Questions and answers on biosimilar medicines, Sept 2012EMA Q&A onBiosimilars
    • 20. Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 20European Commission Consensus Information Paper 2013“It is important to note that biosimilar market uptake has been possible despite thefact that substitution between the biosimilar and its reference medicinal product is notpracticed at the pharmacy level.The decision on whether to substitute a biological medicinal product lies outside theremit of the EMA/CHMP and is the responsibility of the relevant competent authoritieswithin each EU Member State.Since October 2011, pharmacists in Germany maysubstitute, within the framework of the aut idem substitution, biotechnologicallymanufactured products among each other which (a) have been approved withreference to the same reference product and which (b) have been produced by thesame manufacturer with the same manufacturing process. The only differencebetween such substitutable products is their trade name.At the point in time of publication of this consensus information paper, no country hasexplicitly authorized the substitution of biological products from differentmanufacturers, and a number of EU Member States have put legal, regulatory, andpolitical provisions in place that prevent this practice.”Consensus Information Paper 2013. What you need to know about Biosimilar Medicinal Products.http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_report_en.pdf
    • 21. Biologicals and BiosimilarsInterchangeability & Substitution:DefinitionsRegulatory PerspectiveClinical PerspectiveSummary and Conclusions
    • 22. FDA – Scientific Principles of Biosimilar Interchangeability• The possible adoption of scientific standards for biosimilarinterchangeability is unique to the US FDA• The biosimilar applicant must demonstrate through comparableswitching studies that:• their product is biosimilar to the reference product (the foundation)• it can be expected to produce the same clinical result as the referenceproduct in any given patient• (in case of multiple dosing) the risk in terms of safety or diminishedefficacy of alternating or switching between use of the biosimilar and thereference product is not greater than the risk of using the referenceproduct without such alternation or switch*Biologics Price Competition and Innovation Act of 2009 (BPCIA) – U.S. Law22Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars
    • 23. Interchangeability – Key Considerations23Regulatory and Medical Aspects of Interchangeability of Biologicals and BiosimilarsFactors to consider in support of substitution in “Any Given Patient”:•Safety signals during biosimilar development•Known safety issues with reference product•Immunogenicity risk (frequency, severity, anti-drug antibodies)•Safety and efficacy in different indications, especially when indicationextrapolation has occurred•Subpopulations with distinct efficacy or safety issues (e.g. pediatric)•Statistical power to demonstrate equivalent safety and efficacy•Sensitivity of the population or drug to minor changes (e.g. narrowtherapeutic index drugs)Clinical evidence should contribute to totality of the evidence and be basedon a rigorous risk assessment
    • 24. Interchangeability - Switching Study Design 1• Switching studies should follow a cross-over design:• For chronic diseases, both naïve patients and patients on stabletreatment should be studiedBiosimilarReference ProductRegulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 24
    • 25. Interchangeability - Switching Study Design 2• Switching studies should also address alternating (i.e. switchingmore than once)• Issues with Switching Study Designs:• Carry-over effect due to long half lives of most biologics• Ethical and clinical feasibility of long wash-out period• Change in clinical status of the patient over time• Absence of benefit/deterioration of disease state generated by investigationaltreatment regimen• Recruitment issuesBiosimilarReference ProductRegulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 25
    • 26. Interchangeability - Switching Study Considerations• Study duration should be sufficient to capture:• Equivalent efficacy• Time course of pre-defined safety events• Study size and statistical power should ensure:• demonstration of equivalent efficacy• detection of critical safety events including loss of efficacy• Immunogenicity should always be assessed• Drug neutralization or loss of efficacy is one of the major risks associated withswitching• The choice of biologic treatments is often limited for many diseases/patients –lost ground is lost forever• Detection of rare events should be justified by a risk-based approach,including extended “post-interchangeability designation” studiesRegulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 26
    • 27. Interchangeability and Extrapolation• Interchangeability/Substitution cannot be extrapolated fromone tested indication or, if pertinent, a specific patientpopulation to another non-tested one• Clinical data from controlled switching studies should be required foreach labeled indication• A biosimilar may be designated interchangeable in oneindication when interchangeability has been demonstrated forall routes of administration of the reference product for thatparticular indication• However, this may create confusion if products are deemedinterchangeable in one indication, but not in the otherRegulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 27
    • 28. Interchangeability – Post Designation and Pharmacovigilance• Accurate tracking and tracing of adverse events• Substitution between biopharmaceuticals with similar substances mayfurther complicate the linking of an adverse event to a specific drug• Post-marketing surveillance plans should distinguish between treatmentemergent events (including loss of efficacy) due to the biosimilar or to thereference product• Distinct non-proprietary name for biosimilars could help tracking ofadverse events, but would not solve the tracing issueRegulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 28
    • 29. Biologicals and BiosimilarsInterchangeability & Substitution:DefinitionsRegulatory PerspectiveClinical PerspectiveSummary and Conclusions
    • 30. Interchangeability and Substitution of Biosimilars• Current science does not justify interchangeability and substitution for anybiologic, including biosimilars• Approval of a biosimilar product should not be intended to allow forinterchangeability and/or (automatic) substitution with their referenceproduct• Demonstration of interchangeability requires higher standards and additionalclinical data in all indications, and if pertinent, patient populations for whichbiosimilar approval is sought• Switching studies are complex for technical and ethical reasons and very littledata is available on this topic• No studies with switching as the primary endpoint have been performed todate comparing a biosimilar to its reference product• Only a treating physician who has carefully evaluated the consequences of apatient’s response to approved biotherapeutics should make the decision toalter a treatment regime30Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars
    • 31. Thank you!Большое спасибо!Regulatory and Medical Aspects of Interchangeability of Biologicals and Biosimilars 31

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