Pharmacovigilance for Biosimilars

Transcription

1 Pharmacovigilance for Biosimilars Dr. Niraj Chhaya Risk Management, Global Pharmacovigilance Boehringer Ingelheim GmbH 5th Annual Pharmacovigilance Forum, GLC Europe 03 March 2017 Berlin, Germany Disclaimer Contents of this presentation is either personal opinion or compilation from information available in public domain. This does not necessarily represent opinion of Boehringer Ingelheim or Organizers of this meeting.

2 Tighter EU rules on pharmacovigilance for biologicals EMA Adopts New Biologic, Biosimilar Pharmacovigilance Guidance Growth of Biosimilars: Implications for Safety and Risk Management Safety and Risk Management for Biosimilars : A Special Case? Biosimilars and Pharmacovigilance: What You Need to Know and Do Now Changes Afoot at EMA for Biologic and Biosimilar Pharmacovigilance

3 What are biosimilar products? FDA alapplications/therapeuticbiologicapplications/biosimilars/ucm htm

4 What are biosimilar products? EMA

5 Biosimilars marching on

6 List of approved biosimilars - EMA Medicine Name Active Substance Marketing Authorisation Holder Authorisation Date Omnitrope somatropin Sandoz GmbH 12/04/2006 Abseamed epoetin alfa Medice Arzneimittel Pütter GmbH & Co. KG 28/08/2007 Binocrit epoetin alfa Sandoz GmbH 28/08/2007 Epoetin Alfa Hexal epoetin alfa Hexal AG 28/08/2007 Retacrit epoetin zeta Hospira UK Limited 18/12/2007 Silapo epoetin zeta Stada Arzneimittel AG Truxima Celltrion 18/12/2007 Biograstim filgrastim AbZ-Pharma GmbH 15/09/2008 Ratiograstim filgrastim Ratiopharm GmbH 15/09/2008 Tevagrastim filgrastim Teva GmbH 15/09/2008 Filgrastim Hexal filgrastim Hexal AG 06/02/2009 Zarzio filgrastim Sandoz GmbH 06/02/2009 Nivestim Filgrastim Hospira UK Ltd 08/06/2010 Inflectra infliximab Hospira Somatropin UK Limited 10/09/2013 Remsima infliximab Celltrion Epoetin Healthcare alfa Hungary Kft. 10/09/2013 Ovaleap follitropin alfa Teva Pharma B.V. 27/09/2013 Grastofil filgrastim Apotex Epoetin Europe BV zeta 18/10/2013 Bemfola follitropin alfa Finox Biotech Filgrastim AG 27/03/2014 Abasaglar insulin glargine Eli Lilly Regional Operations GmbH 09/09/2014 Infliximab Accofil filgrastim Accord Healthcare Ltd 18/09/2014 Benepali etanercept Samsung Follitropin Bioepisalfa UK Limited 14/01/2016 Flixabi infliximab Samsung Insulin Bioepis glargine UK Limited (SBUK) 26/05/2016 Thorinane Enoxaprin sodium Pharmathen S.A. 15/09/2016 Inhixa Enoxaprin sodium TechdowEtanercept Europe AB 15/09/2016 Lusduna insulin glargine Merck Sharp & Dohme Limited 04/01/2017 Enoxaparin

7 List of approved biosimilars - FDA Product Name Proprietary Name Authorisation Date filgrastim-sndz Zarxio 06-Mar-2015 infliximab-dyyb Inflectra 05-Apr-2016 etanercept-szzs Erelzi 30-Aug-2016 Adalimumab Filgrastim Infliximab Etanercept adalimumab-atto amjevita 23-Sep-2016

8 Globally Adalimumab Darbepoetin Epo-alfa Epo-kappa Etanercept Filgrastim Infliximab Insulin glargine Somatropin Trastuzumab

9 Biosimilar Development vis-à-vis British Journal of Clinical Pharmacology, RU R1, 4 JUN 2015 DOI: /bcp de Mora, F. (2015) Biosimilar: what it is not. Br J Clin Pharmacol, 80:

10 Biosimilars: Pharmacovigilance Traceability No clinically meaningful differences Interchangeability Immunogenicity Labeling Nomenclature Risk Management Plans Totality of evidence Post approval safety monitoring

11 Traceability

12 Traceability Traceability of Biopharmaceuticals in Spontaneous Reporting Systems: A Cross-Sectional Study in the FDA Adverse Event Reporting System (FAERS) and EudraVigilance Databases N. S. Vermeer et al, Drug Saf (2013) 36:

13 Traceability Traceability of Biopharmaceuticals in Spontaneous Reporting Systems: A Cross-Sectional Study in the FDA Adverse Event Reporting System (FAERS) and EudraVigilance Databases N. S. Vermeer et al, Drug Saf (2013) 36:

14 Traceability Brand name and batch number reporting of recombinant biologics by product class in adverse drug reaction (ADR) reports received by the Netherlands Pharmacovigilance Centre Lareb ( ) Product class ADRs reported [n] Brand names reported [n (%)] Batch numbers reported [n (%)] Somatropins 4 3 (75) 0 (0) Epoetins (93) 0 (0) Filgrastims (89) 1 (5) Follitropins (100) 1 (5) Monoclonal antibodies (67) 45 (6) Insulins (91) 18 (10) Interferons (88) 3 (6) Antihaemophilic factors (100) 1 (2) Fusion proteins (77) 5 (2) Enzymes 2 1 (50) 0 (0) Other (78) 0 (0) Total (76) 74 (5) Traceability of Biologics in The Netherlands: An Analysis of Information-Recording Systems in Clinical Practice and Spontaneous ADR Reports. K. Klein et al, Drug Safety, 2016; 39:

15 Traceability - GVP module* Significant coverage about Traceability in GVP module key requirement for pharmacovigilance of biologicals Recording and reporting of name/batch information at all levels in supply chain from manufacturer release till patient administration. All SmPCs should include a prominent statement that the name and batch number of administered product should be clearly recorded in the patient file. It recommends the use of sticky/tear-off labels in the product packaging and encourages the use of available barcode technology. * European Medicines Agency (EMA): Guideline on good pharmacovigilance practices (GVP) Product- or Population-Specific Considerations II: Biological medicinal products, August 2016

16 Interchangeability

17 Interchangeability (1) FDA - Information for Consumers (Biosimilars) 2015 (2) European Commission - Consensus Information Paper. What you need to know about Biosimilar Medicinal Products 2013

18 Interchangeability EU: Interchangeability decision at national level EMA Automatic substitution: Concerns regarding traceability, Repeated switches between biosimilar and reference biological may increase immunogenicity An interchangeable biological product is biosimilar to an FDA-approved reference product and meets additional standards for interchangeability. FDA FDA requires licensed biosimilar and interchangeable biological products to meet the Agency s rigorous standards of safety and efficacy. That means patients and health care professionals will be able to rely upon the safety and effectiveness of the biosimilar or interchangeable product, just as they would the reference product.

19 Biosimilar substitution - EU Biosimilar substitution policies: an Overview, Mendoza C et al, ISPOR 18th Annual European Congress, Milan, Italy, 7-11 November, 2015

20 Biosimilar substitution - US

21 Interchangeability The choice of treatment: a clinical decision entrusted to the prescribing physician Countries without specific provisions or guidelines: automatic substitution because of economic reasons Guidelines, rules, laws are being developed slowly and steadily globally

22 Immunogenicity

23 Immunogenicity Product related Choice of cell line Post translational changes Impurities Choice of product containers Patient / Disease related Genetic background Concomitant medications Nature of underlying disease Immune status Immunogenicity Treatment related Route of administration Dosing frequency

24 Immunogenicity 1) Biotechnology derived proteins may induce unwanted immune responses, influenced by various factors: patient- and disease-related, product-related. 2) Risk-based approach to immunogenicity: the extent and type of preauthorisation immunogenicity studies and post-marketing risk management program are tailored according to the risk of immunogenicity and the severity of its potential or observed consequences. 3) Assays: - Adequate screening and confirmatory assays to measure immune responses against a therapeutic protein. - Assays capable of distinguishing neutralizing from non-neutralizing antibodies - Validated assays that are used in pivotal clinical trials and in postauthorisation studies 5) Clinical setting: Integrated analysis of immunological, pharmacokinetic, clinical efficacy and safety data 6) Immunogenicity issues should be addressed in Risk Management Plans. 7) Planning and evaluation of immunogenicity is a multidisciplinary exercise. EMA: DRAFT Guideline on Immunogenicity assessment of biotechnology-derived therapeutic proteins September 2015

25 Immunogenicity Recommendations for immunogenicity risk mitigation in clinical phase of development of therapeutic protein products 1) Development of assays for anti drug antibody 2) Product specific antibody sampling considerations 3) Dosing 4) Adverse events - Real time assessments for antibodies during clinical trial - Clinically relevant immune responses: Study the underlying mechanism and identify any contributing factors (may lead to modification of product formulation, screening of high risk patients) - Sponsors may choose to explore premedication, desensitization or immune tolerance induction procedures as potential risk mitigation strategy 5) Comparative immunogenicity studies 6) Postmarketing safety monitoring - Postmarketing surveillance - Postmarketing clinical trials focused on immunogenicity FDA: Guidance for industry - Immunogenicity Assessment for Therapeutic Protein Products August 2014

26 Immunogenicity: GVP Module* More complex nature of biologicals: greater potential risk of immunogenicity as compared to non-biologicals Most cases: Transient appearance of antibodies without clinical significance Some occasions: Serious and life-threatening reactions This chapter: Immunogenicity refers to an unwanted immune response that is considered potentially clinically relevant and may require product-specific pharmacovigilance and risk management activities Limitations of Immunogenicity evaluation pre-authorization due to limited sample size and rarity of disease to be treated. This uncertainty should be reflected in RMP and requires specific activities in post-authorization phase as appropriate. * European Medicines Agency (EMA): Guideline on good pharmacovigilance practices (GVP) Product- or Population-Specific Considerations II: Biological medicinal products, August 2016

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28 Risk Management Very important, Increasing regulatory burden but worth it! In the interest of patients, industry and agencies: Least harm, Maximum benefits Strategies: US REMS and EU RMP Channelize drug developers for greater consideration to how patients can avoid some adverse reactions to drugs and achieve better tolerance, by paying attention to criteria such as contraindications, warnings and precautions The EU RMP is an engagement of wider scope, and is binding on a wider set of medicines than the US REMS.

29 REMS - US

30 EU RMP: Additional PV activities Biosimilar Comparator generic (brand) Epoetins Additional pharmacovigilance activities HX575 (Abseamed, Binocrit & Epoetinα Hexal) Epoetin-α(Eprex) 1) Cohort study to monitor incidence of thromboembolic events 2) Survey to establish (off-label) subcutaneous use SB-309 (Retacrit & Silapo) Epoetin-α(Eprex) 1) Close monitoring using specific questionnaires to establish PRCA and thromboembolic events 2) Study to evaluate safety and tolerability of epoetin zeta administered intravenously for the maintenance treatment of renal anemia (CT ) 3) Post-authorization cohort study of epoetin zeta for the treatment of renal anemia (PMS ) 4) Prospective open, noncontrolled, multicenter study to evaluate safety and tolerability of epoetin zeta administered subcutaneously for the treatment of anemia in cancer patients (CT ) 5) Drug utilization study on use of epoetin zeta Interchangeability, immunogenicity and biosimilars; Hans C Ebbers, Stacy A Crow, Arnold G Vulto & Huub Schellekens, Nature Biotechnology 30, (2012) doi: /nbt.2438

31 EU RMP: Additional PV activities Biosimilar XM02 (Biograstim, Filgrastim Ratiopharm, Ratiograstim & Tevagrastim) EP2006 (Zarzio & Filgrastim Hexal) PLD108 (Nivestim) Comparator generic (brand) Filgrastim (Neupogen) Filgrastim (Neupogen) Filgrastim (Neupogen) G-CSFs Additional pharmacovigilance activities 1) Signal detection procedure for all incoming adverse drug response reports from whatever sources (including the SCNIR) and indications, and scheduled antibody assessment in case of suspected immunogenicity 2) Cooperation with SCNIR and analysis of corresponding Biograstim-SCNIR data 1) Pharmacovigilance program for patients with severe chronic neutropenia 2) A 12-month, phase 4 study in patients with severe neutropenia, followed by a five-year safety follow-up of study patients in cooperation with the SCNIR 3) Five-year safety follow-up study of healthy stem cell donors in cooperation with apheresis centers 1) Targeted questionnaire 2) Follow-up of patients through SCNIR registry 3) Cooperative program with hematological transplant centers 4) Specialized follow-up for long-term data Interchangeability, immunogenicity and biosimilars; Hans C Ebbers, Stacy A Crow, Arnold G Vulto & Huub Schellekens, Nature Biotechnology 30, (2012) doi: /nbt.2438

32 EU RMP: Additional PV activities Biosimilar Comparator generic (brand) Human growth hormones Additional pharmacovigilance activities Omnitrope Somatropin (Genotropin) 1) Phase 4 prospective, single-arm clinical trial in children born short for gestational age (part of registry reviewing patient demographics, long-term safety and immunogenicity) 2) Prolongation of ongoing phase 3 study EP2K-02-PhIIIlyo to provide long-term immunogenicity data 3) Immunogenicity testing for children enrolled in registry as appropriate (e.g., loss of efficacy) 4) Registry of patients reviewing patient demographics, longterm safety including malignancy and other safety issues Valtropin (withdrawn for commercial reasons in 2012) Somatropin (Humatrope) 1) Registry (two years' treatment): patient demographics, adverse events and laboratory parameters 2) Generation of further immunogenicity data Interchangeability, immunogenicity and biosimilars; Hans C Ebbers, Stacy A Crow, Arnold G Vulto & Huub Schellekens, Nature Biotechnology 30, (2012) doi: /nbt.2438

33 Infliximab biosimilar - PV Plan (as published in Risk Management Plan) Post Marketing Surveillance study Sponsor funded registries (Adult RA, Adult and Pediatric IBD patients) and participation in already established registry (RA) Participation in British Society for Rheumatology Biologics Register - Rheumatoid Arthritis (BSRBR-RA) (UK) Clinical trial in additional indication Prospective cohort studies in various indications (RA, UC, CD) 33

34 RMP: GVP module* For biosimilars and related products, the summary of safety concerns should, as a minimum, be the same as the reference product unless otherwise justified. RMP Module SVI: potential for infections caused by residuals of biological material used in the manufacturing process as well as contaminations introduced by the manufacturing process should be presented in relation to the potential for transmission of infectious agents. RMP Part III (PV plan): need and plans for continuous life-cycle signal detection and pharmacovigilance specific to the product including batchspecific issues, particularly following a significant change to the manufacturing process. Additional PV activities: Measures to support traceabilty, activities to measure background rates of AESIs, Observed Vs Expected SAR analysis, post authorization safety studies including registries. * European Medicines Agency (EMA): Guideline on good pharmacovigilance practices (GVP) Product- or Population-Specific Considerations II: Biological medicinal products, August 2016

35 Risk Management Plan (RMP)

36 Robust postmarket safety monitoring is an important component in ensuring the safety and effectiveness of biological products, including biosimilar therapeutic protein products. Scientific Considerations in Demonstrating Biosimilarity to a Reference Product Guidance for Industry FDA, April 2015

37 1) Data repository on biologics and biosimilars 2) Trace Trace Trace At all levels in supply chain from manufacturer release till patient administration 3) Clinically: Clear understanding of Residual Effect Period, Impact of immunogenicity related events 4) Robust and optimal Risk Management Plan (RMP) 5) Optimal practical clinical trial design for establishing interchangeability to meet expectations of all relevant stakeholders 6) Robust Post marketing safety monitoring Phase IV clinical trials, Observational trials, NTAs, Post marketing surveillance, Investigator initiated trials, Registries

38 Thank You Long way to go Or