International Federationof PharmaceuticalManufacturers & AssociationsPharmacovigilance Aspects ofBiotherapeutic medicines:...
Agenda• Setting the scene– Changing regulations – a brave new world• Pharmacovigilance Challenges related to Biotherapeuti...
Pharmacovigilance today• Systems developing at different rates, with different requirements– Many countries still without ...
New pharmacovigilance legislation adopted in the EU inDecember 2010 will promote and protect public health andsave potenti...
A brave new world of changing regulations:Understanding benefit-risk16 May 2013 © IFPMA 20135MoreDefinedUncertainPhase 3Tr...
Challenge 1: Biotherapeutics differ fromchemically-synthesized molecules in bothcomplexity & sensitivityImage Source: Tim ...
• One of the key factors that distinguishes bothbiotherapeutic and biosimilar medicines from low-molecular-weight pharmace...
Approaches to addressImmunogenicity16 May 2013 © IFPMA 20138
Areas Potential clinical outcomeSafety • Hypersensitivity reactions• Receptor signaling related to cross-linking• Neutrali...
No predictability of Immunogenicityfrom preclinical to clinical• Immunogenicity - The immunogenicity ofmAbs is complex and...
Challenge 3: Exaggerated Pharmacology11Hansel et al, Nat Rev Drug Discov. 2010 16 May 2013 © IFPMA 2013• The nature of saf...
Exaggerated PharmacologySafety Issue Explanationtuberculosis with the use oftumour necrosis factor (TNF)-ainhibitors, espe...
Challenge 4: Different regulatory pathways13 16 May 2013 © IFPMA 2013
Comprehensive pharmacovigilance andrisk management planning needed forall biotherapeutics• Even minor differences in the m...
Different regulatory pathwaysInterchangeability/Substitution• Not all products will be approved for allindications• Automa...
Different regulatory pathwaysImportance to “track & trace”• Mix of biotherapeutics in use for the sametreatment, some with...
Acknowledged by the regulators: Increasedemphasis on identification and tracking ofbiotherapeutics in pharmacovigilance sy...
Traceability16 May 2013 © IFPMA 201320
Issues in practice also emphasizeimportance of PV for biotherapeutics• Biotherapeutics often used for chronictreatment– Sw...
Tracking and tracingbiotherapeutics – challenges for theINN system• INN plays a central role in:– National pharmacovigilan...
In Summary• Due to their unique product characteristics and practicesin prescribing and use, all biotherapeutics – innovat...
International Federationof PharmaceuticalManufacturers & AssociationsThank you!16 May 2013 © IFPMA 201324
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24. Dr. Thomas Schreitmueller - F. Hoffman-La Roche (on behalf of IFPMA)

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Illustrates key pharmacovigilance considerations for biotherapeutic medicines “Pharmacovigilance Aspects of Biotherapeutic medicines:Nowadays and Perspectives”

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  • References 1. Niederwieser, Deitger and Schmitz, Stephan. Biosimilar agents in oncology/haematology: from approval to. European Journal of Haematology. 2010, Vol.86. 2. EuropaBio. Guide to Biological Medicines. A Focus on Biosimilar Medicines. EuropaBio. [Online] October 26, 2011. [Cited: August 23, 2012.] http://www.europabio.org/guide-biological-medicines-focus-biosimilar-medicines. 3.World Health Organization. Expert Committee on Biological Standardization. Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs). World Health Organization. [Online] October 23, 2009. [Cited: March 23, 2012.] http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf. 4. European Medicines Agency. Guideline on similar biological medicinal products containing biotechnology-derived proteins as active substance: quality issues (revision 1). European Medicines Agency - Europa. [Online] May 24, 2012. [Cited: August 23, 2012.] http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/05/WC500127960.pdf.
  • 24. Dr. Thomas Schreitmueller - F. Hoffman-La Roche (on behalf of IFPMA)

    1. 1. International Federationof PharmaceuticalManufacturers & AssociationsPharmacovigilance Aspects ofBiotherapeutic medicines:Nowadays and PerspectivesDr Thomas Schreitmueller, F. Hoffmann - La RocheOn behalf of IFPMA Biotherapeutics Group16 May 2013 © IFPMA 20131
    2. 2. Agenda• Setting the scene– Changing regulations – a brave new world• Pharmacovigilance Challenges related to Biotherapeutics– Biotherapeutics differ from chemically-synthesizedmolecules– Immunogenicity– Exaggerated Pharmacology & Rare Events– Different regulatory pathways• Traceability• Conclusions16 May 2013 © IFPMA 20132
    3. 3. Pharmacovigilance today• Systems developing at different rates, with different requirements– Many countries still without strong pharmacovigilance systems– INN system weakening, different approaches to naming atnational levels• Focus on the development of comprehensive pharmacovigilancesystems including:– Need to establish basic pharmacovigilance guidance to ensurepatient safety– Improving identification, naming of products, record keeping– Increased emphasis on robust adverse eventcollection/reporting, surveillance, signal detection and evaluation– Focus on risk in context of benefit• Important to take the entire prescription/dispensing/using/ADR reporting chaininto consideration for traceability3 16 May 2013 © IFPMA 2013
    4. 4. New pharmacovigilance legislation adopted in the EU inDecember 2010 will promote and protect public health andsave potentially thousands of lives each year by:•strengthening the European system for monitoring thesafety and use of medicines•clarifying and simplifying tasks for the parties involved;•improving decision-making procedures and reducingadministrative costs•strengthening communication and transparency on thesafety of medicinesPatient SafetyChanging Regulations16 May 2013 © IFPMA 20134
    5. 5. A brave new world of changing regulations:Understanding benefit-risk16 May 2013 © IFPMA 20135MoreDefinedUncertainPhase 3TrialPopulation Label PopulationOff-label & NoncompliantPopulationOptimizeIndividualizedPopulationPersonalizedHealth Care(biomarker,Bioimaging, …)Benefit/RiskEfficacy-Effectiveness GapLack ofcommunicationLack ofexternal validityHow to BestManage ThisTransition?Benefit Risk Management PlansAdapted from Thomas Lundgrenn (DIA QPPV Forum, 17-18 April 2013)
    6. 6. Challenge 1: Biotherapeutics differ fromchemically-synthesized molecules in bothcomplexity & sensitivityImage Source: Tim Osslund photographer (Amgen staff); Amgen Usage Rights: Unlimited world-wide usage rights for an unlimited time. Imagesnot to scale.1.Prugnaud JL. Similarity of biotechnology-derived medicinal products: specific problems and new regulatory framework Br J Clin Pharmaco l.2007;65:619-620;2.Roger SD. Nephrology. 2006;11:341-3463.Sharma BG. Manufacturing challenges for biosimilars – the process defines the product. EJHP Practice. 2007;13:54-56.Biotherapeutics Small Molecules6 © IFPMA 201316 May 2013
    7. 7. • One of the key factors that distinguishes bothbiotherapeutic and biosimilar medicines from low-molecular-weight pharmaceuticals and generic drugs istheir capacity to elicit an immune response• Immunogenicity is the production of host anti-bodiesdirected against a therapeutic (anti-therapeuticantibodies, ATA = anti-drug antibodies, ADA)Challenge 2: Immunogenicity16 May 2013 © IFPMA 20137Chirmule et al, The AAPS Journal 2012
    8. 8. Approaches to addressImmunogenicity16 May 2013 © IFPMA 20138
    9. 9. Areas Potential clinical outcomeSafety • Hypersensitivity reactions• Receptor signaling related to cross-linking• Neutralizing activity of endogenouscounterpartEfficacy • Neutralization• Impact PK• Change in biodistributionNone • Despite generation of antibodies, nodiscernible impactPotential Consequences ofImmunogenicity16 May 2013 © IFPMA 20139
    10. 10. No predictability of Immunogenicityfrom preclinical to clinical• Immunogenicity - The immunogenicity ofmAbs is complex and there are a numberof often poorly understood factors whichmake it difficult to predict with anycertainty whether a therapeutic ordiagnostic monoclonal antibody is likely toprovoke a clinically relevant immuneresponse*16 May 2013 © IFPMA 201310* EMA Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use
    11. 11. Challenge 3: Exaggerated Pharmacology11Hansel et al, Nat Rev Drug Discov. 2010 16 May 2013 © IFPMA 2013• The nature of safety problems identified after approval forbiologicals is often related to the immunomodulatory effecte.g infections (Giezen et al. JAMA 2008)• Adverse events are related to exaggerated pharmacology,e.g TB with Infliximab (Giezen et al, Drug Safety 2009)11
    12. 12. Exaggerated PharmacologySafety Issue Explanationtuberculosis with the use oftumour necrosis factor (TNF)-ainhibitors, especially InfliximabTNFa has a role in the immuneresponse to the mycobacteriaresponsible for tuberculosis.Inhibition of TNFa will lead to anincrease of the activity of the bacilliand cause diseasedramatically increased incidence ofpure red cell aplasia in patientstreated with one particularformulation of recombinant humanepoetinimmunogenic response toendogenousmolecules, which occurredfollowing changes in themanufacturing of epoetin alfaGiezen et al. Drug Safety 200916 May 2013 © IFPMA 201312
    13. 13. Challenge 4: Different regulatory pathways13 16 May 2013 © IFPMA 2013
    14. 14. Comprehensive pharmacovigilance andrisk management planning needed forall biotherapeutics• Even minor differences in the manufacturingprocess may affect the efficacy and/or safetyprofile– Innovator Products– SBPs may have potential for different safety profile thaninnovator– Non-comparable biotherapeutics - different safety and efficacyprofiles compared to other biotherapeutics of the same productclass possibly due to lack of comparability information, i.e.unknown whether and which physicochemical differences exist(Weise, M., et al.)16 May 2013 © IFPMA 201314
    15. 15. Different regulatory pathwaysInterchangeability/Substitution• Not all products will be approved for allindications• Automatic substitution of biological productsis not compatible with high levels of patientsafety• Right of the prescriber (physician) and of thepatient to choose appropriate product basedon proper and transparent information16 May 2013 © IFPMA 201315
    16. 16. Different regulatory pathwaysImportance to “track & trace”• Mix of biotherapeutics in use for the sametreatment, some with the same INN• Biotherapeutics with the same INN could have– Different posology– Different indicationsHow to track and trace the medicine which anygiven patient has received? Identification Records Physician and patient awareness16 May 2013 © IFPMA 201316
    17. 17. Acknowledged by the regulators: Increasedemphasis on identification and tracking ofbiotherapeutics in pharmacovigilance systemsArticle 102(e) of the Medicinal Products Directive 2011/83/EU, as amended byDirective 2010/84/EU, deals with the identification of medicinal products whenreporting adverse events. Article 102(e) provides clarification specifically forbiological medicinal products.The Member States shall:(e) Ensure, through the methods for collecting information and where necessarythrough the follow-up of suspected adverse reaction reports, that all appropriatemeasures are taken to identify clearly any biological medicinal productprescribed, dispensed, or sold in their territory which is the subject of asuspected adverse reaction report, with due regard to the name of the medicinalproduct, in accordance with Article 1(20), and the batch number [Emphasis added].Example: New EU Requirement in EUGVP Module VI requires MAH to follow up until batch number,brand name and active substance are known19 16 May 2013 © IFPMA 2013
    18. 18. Traceability16 May 2013 © IFPMA 201320
    19. 19. Issues in practice also emphasizeimportance of PV for biotherapeutics• Biotherapeutics often used for chronictreatment– Switching therapies• Physician and patient awareness• PV system requirements – necessary details to recordbeyond INN (e.g. brand name, unique identifier, batchnumber, etc)– Implications for effective pharmacovigilance• Frequency of switches• Managing track and trace, analysis21 16 May 2013 © IFPMA 2013
    20. 20. Tracking and tracingbiotherapeutics – challenges for theINN system• INN plays a central role in:– National pharmacovigilance and traceability systems– National systems for substituting medicines• Limited control over use of existing INNs– Applicant decides if new INN wanted/required– If existing INN is chosen, National Regulators need to ensureimplementation of WHO naming system• Under current WHO criteria, possible for multiplebiologics to have the same INN with different clinicalcharacteristics• As a result: no clear INN differentiation betweensimilar products22 16 May 2013 © IFPMA 2013
    21. 21. In Summary• Due to their unique product characteristics and practicesin prescribing and use, all biotherapeutics – innovator,SBPs and non-comparable biotherapeutics – requirecomprehensive pharmacovigilance guidance andsystems• Effective, global pharmacovigilance for patient safetyrequires that we:1. IdentifyNaming,distinguishableINN2.Recordation/ReportingSpontaneousreporting,Periodic reportsRobust dataPatient Records3. Monitor and AssessSafety signals identified, explored23 © IFPMA 201316 May 2013
    22. 22. International Federationof PharmaceuticalManufacturers & AssociationsThank you!16 May 2013 © IFPMA 201324

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