17. Gino Grampp - Amgen


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

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17. Gino Grampp - Amgen

  1. 1. International Federation of Pharmaceutical Manufacturers & Associations Biotherapeutic medicines and pharmacovigilance Dr Gino Grampp, Amgen On behalf of IFPMA Biotherapeutics Group 1 20 November 2013 © IFPMA 2013
  2. 2. Agenda • Setting the scene – Changing regulations – a brave new world • Pharmacovigilance challenges related to biotherapeutics • Identification and traceability 2 20 November 2013 © IFPMA 2013
  3. 3. Pharmacovigilance today • • Systems developing at different rates, with different requirements – Many countries still without strong pharmacovigilance systems – INN system for biotherapeutics weakening, different approaches to naming at national levels – Need for robust PV systems and consistent approach to naming to allow countries to leverage global PV data Focus on the development of comprehensive pharmacovigilance systems including: – Need to establish basic pharmacovigilance guidance to ensure patient safety – Improving identification, naming of products, record keeping – Increased emphasis on robust adverse event collection/reporting, surveillance, signal detection and evaluation – Focus on risk in context of benefit • Important to take the entire prescription/dispensing/using/ADR reporting chain into consideration for traceability 3 20 November 2013 © IFPMA 2013
  4. 4. Policy-makers are emphasizing enhanced pharmacovigilance of biotherapeutics European Community 2011 PV Legislation1 FDA is Considering Policies for the U.S.2 “The Member States shall: (e) Ensure […] that all appropriate measures are taken to identify clearly any biological medicinal product prescribed, dispensed, or sold in their territory…” “The FDA process for biosimilars must include product specific safety monitoring […] and appropriate strategies must be developed to ensure the implementation of robust, modern pharmacovigilance programs for biologics.” 1. Article 102(e) of the Medicinal Products Directive 2011/83/EU, as amended by Directive 2010/84/EU. 2. Kozlowski S et al. N Engl J Med. 2011;365:385-388. 4 20 November 2013 © IFPMA 2013
  5. 5. Challenge 1: Biotherapeutics differ from chemically-synthesized molecules in both complexity & sensitivity Biotherapeutics 5 Small Molecules Image Source: Tim Osslund photographer (Amgen staff); Amgen Usage Rights: Unlimited world-wide usage rights for an unlimited time. Images not 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; 20 November 2013 2. Roger SD. Nephrology. 2006;11:341-346 3. Sharma BG. Manufacturing challenges for biosimilars – the process defines the product. EJHP Practice. 2007;13:54-56. © IFPMA 2013
  6. 6. Challenge 2: Immunogenicity • One of the key factors that distinguishes biotherapeutic medicines from low-molecular-weight pharmaceuticals is their capacity to elicit an immune response • Immunogenicity is the production of host antibodies directed against a therapeutic (anti-drug antibodies, ADA) • Rates of immunogenicity vary by product and condition of use (from <1% to >50%)1,2 • ADAs may have no clinical impact, may impact bioavailability, or may impact safety and efficacy1,2,3 3. Koren, E., et al. (2002). “Immune Responses to Therapeutic Proteins in Humans - Clinical Significance, Assessment and Prediction.” Current Pharmaceutical Biotechnology 3(4): 349-360. Purcell, RT and Lockey, RF. (2008). “Immunologic Responses to Therapeutic Biologic Agents.” Journal of Investigational Allergololgy & Clinical Immunology 8(5): 335-342 Chirmule, N., et al. (2012). "Immunogenicity to Therapeutic Proteins: Impact on PK/PD and Efficacy." The AAPS Journal 14(2): 296-302. 6 20 November 2013 1. 2. © IFPMA 2013
  7. 7. Challenge 3: Complex pharmacology • Complex biotherapeutics (e.g. monoclonal antibodies) can modulate immunological functions through multiple mechanisms • The nature of safety problems identified after approval for biologicals is often related to the immunomodulatory effect e.g. infections (Giezen et al. JAMA 2008) 7 7 Hansel et al, Nat Rev Drug Discov. 2010 20 November 2013 © IFPMA 2013
  8. 8. Challenge 4: Limited predictability of analytical and preclinical to clinical Analytical and preclinical studies cannot reliably predict immunogenicity, pharmacology or safety of biotherapeutics • Immunogenicity: currently animal models cannot predict clinical immune response to impurities (e.g. protein aggregates)1,2 • Pharmacology: animal models cannot reliably predict structural effects on pharmacology (PK and PD)3 • Safety: Off-target and immunomodulatory effects are often species specific – Eg. Cytokine storm occurring in healthy volunteers treated with the superagonist anti-CD28 monoclonal antibody TGN1412 (TeGenero)4 1.EMA Guideline on immunogenicity assessment of monoclonal antibodies intended for in vivo clinical use 2. Ponce et al. Regulatory Toxicology and Pharmacology 54 (2009) 164–182 3. Carter. Nat Rev Immunol. 2006;6:343-357. 4. Sathish et al. Nat Rev Drug Disc. 2013;12:306-324 8 20 November 2013 © IFPMA 2013
  9. 9. Challenge 5: Different regulatory pathways Originator Biotherapeutic • Novel product, generally with patent protection • Marketing authorisation through full regulatory dossier Similar Biotherapeutic Product (SBP) • Product highly similar to an originator biotherapeutic that has already been authorized (reference medicinal product) • Subject to a tailored regulatory data package establishing biosimilarity through comprehensive comparability exercise 9 20 November 2013 Non-comparable Biotherapeutic • Product that is not approved in accordance with the WHO SBP guidelines, e.g. • Product developed on its own and not directly compared and analyzed against a licensed reference product • May or may not have been compared clinically • Can be subject to regulatory approval, but in some settings of a more abbreviated nature • Products with unclear approval standards © IFPMA 2013
  10. 10. What is an SBP (aka “biosimilar”)? • As their name implies, SBPs are “similar” but not identical versions of their innovative reference biotherapeutic product (RBP) • Whereas producing generic versions of off-patent chemically-synthesized medicines is relatively easy, producing an SBP is far more complicated due to the complex molecular structure and the unique manufacturing process required for biotherapeutic medicines • Due to their manufacturing process and complexity, all SBPs differ from the originator product and from each other and therefore regulatory assessment should ensure that the inevitable differences do not lead to clinically meaningful differences. Original Biotherapeutic 1. 10 SBPs Neiderwieser D, Schmitz S. Biosimlar agents in oncology/haematology; from approval to practice. Eur J Haematol. 2011 Apr;86(4):277-88 20 November 2013 © IFPMA 2013
  11. 11. Different regulatory pathways Implications for pharmacovigilance • • Many countries now have regulatory pathways for biologics and biosimilars which are aligned with WHO related guidelines – However, some jurisdictions have stand alone pathways defined differently – For example, stand alone pathways for related biologics, but without comparability This results in multiple sources of biotherapeutics in use for the same treatment, some with the same INN – • E.g. Interferon beta-1a, interferon beta-1b Biotherapeutics using the same INN could have – Different posology – Different indications – Different safety profiles How to identify and trace the medicine which any given patient has received?  Identification  Records  Physician and patient awareness 11 20 November 2013 © IFPMA 2013
  12. 12. Comprehensive pharmacovigilance and risk management planning needed for biotherapeutics • Even minor differences in the manufacturing process may affect the efficacy and/or safety profile – Originator Products – SBPs may have potential for different safety profile than originator – Non-comparable biotherapeutics - different safety and efficacy profiles compared to other biotherapeutics of the same product class possibly due to lack of comparability information, i.e. unknown whether and which physicochemical differences exist (Weise, M., et al.)2 • Biotherapeutics often used for chronic treatment – Switching therapies can confound pharmacovigilance, especially in the case of latent immunogenicity2 1. Wiese M et al. Biosimilars – why terminology matters. Nat. Biotech. 2011;29:690-693 2. Wieser C, Rosenkranz A. Clin. Kidney J. 2013;6:164–182 12 20 November 2013 © IFPMA 2013
  13. 13. Example: Important differences in Interferon beta-1a • Published reports show differences in purity and potency among originator and non-comparable versions of interferon beta-1a • Recall non-comparables have not been assessed through WHO-aligned SBP pathway Purity by SDS-PAGE Potency by In vivo Bioassay Originators Non-comparables Presented by Regina Buffels, Biogen Idec, World Biosimilar Congress EU, London 2012 and Adapted from Meager et al. J of Interferon and Cytokine Research 2011;31:383-392 13 20 November 2013 © IFPMA 2013
  14. 14. Do interferon beta-1a differences matter? Interim analysis of an observational study • MATRIX phase 4 study performed in 2 Latin American countries comparing antibodies (NAbs), PD markers, and treatment-related events in originator (A) and non-comparable (B) IFN-beta • Enrolment targets: 90 MS patients per arm, with 1-3 years prior exclusive use of either A or B Some study findings: • Low enrolment due to common pharmacy substitution of (B) for (A) • NAbs not detected – probably due to low patient numbers • PD marker higher in cohort A (P<0.01) • Flu like symptoms higher in cohort A (P<0.01) Presented by Regina Buffels, Biogen Idec, World Biosimilar Congress EU, London 2012 Abstract by C. Cuevas at 28th Congress of the European Committee for Treatment and Research in Multiple Sclerosis, 10-13 October 2012, Lyon, France 14 20 November 2013 © IFPMA 2013
  15. 15. Traceability Systems should encourage recording details beyond INN (e.g. brand name, unique identifier, batch number, etc) 15 20 November 2013 © IFPMA 2013
  16. 16. IFPMA supports the goal of the INN system • IFPMA continues to share WHO's goal in preserving the objectives of the INN system: • • • • Unique and universally-available designated name for each active substance to be marketed as a pharmaceutical Clear identification; and Safe prescribing and dispensing Biotherapeutic medicines need to be identifiable throughout the prescribing and dispensing processes to promote patient safety • • 16 In practice this is not occurring with the current INN system IFPMA welcomes WHO action on this issue to promote a globally harmonized & distinguishable naming system for biotherapeutics to promote clear identification and effective track-and-trace of each distinct biotherapeutic medicine • IFPMA supports publication of a proposal for implementation of a distinguishable INN for © IFPMA 2013 all biotherapeutics, including a unique product identifier
  17. 17. In Summary • Due to their unique product characteristics and practices in prescribing and use, all biotherapeutics – originator, SBPs and non-comparable biotherapeutics – require comprehensive pharmacovigilance guidance and systems • Regulatory authorities can support effective pharmacovigilance through: Nomenclature 1. Identification Brand name prescribing and/or distinguishable INN for biotherapeutics 17 Systems Advocacy 2. Reporting & analysis 3. Build Support Spontaneous reporting; Multiple identifiers Periodic reports Safety signals identified, explored Education; Active participation with stakeholders 20 November 2013 © IFPMA 2013
  18. 18. International Federation of Pharmaceutical Manufacturers & Associations Thank you! 18 20 November 2013 © IFPMA 2013
  19. 19. Industry support for unique identifier Presented by IFPMA at Open Session to Stakeholders: 57th Consultation on International Nonproprietary Names (INN) for Pharmaceutical Substances, October 22, 2013
  20. 20. Tracking and tracing biotherapeutics – challenges for the INN 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 ensure implementation of WHO naming system • Under current WHO criteria, possible for multiple biologics to have the same INN with different clinical characteristics • As a result: no clear INN differentiation between similar products 20 16 May 2013 © IFPMA 2013