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9 Karin Heidenreich -  Novartis
 

Tuesday, 19 November, 2013

Tuesday, 19 November, 2013
Latin America Biotherapeutic Conference Day 1

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    9 Karin Heidenreich -  Novartis 9 Karin Heidenreich - Novartis Presentation Transcript

    • Biosimilars: Principles of their Development and Evaluation Dr. Karin Heidenreich / Global Public Policy R&D Novartis International AG, Switzerland Workshop on Biotherapeutics & Biosimilars Lima/Peru on 19 November 2013
    • Disclaimer The following presentation contains forward-looking statements that can be identified by terminology such as such as “potential,” “expected,” “will,” “planned,” or similar expressions, or by express or implied discussions regarding potential new products, potential new indications for existing products, or regarding potential future revenues from any such products; potential outcomes of our efforts to improve the quality standards at any or all of our manufacturing sites; or regarding potential future sales or earnings of the Group or any of its divisions in the near- and long-term; or by discussions of strategy, plans, expectations or intentions. You should not place undue reliance on these statements. Such forward-looking statements reflect the current views of the Group regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that any new products will be approved for sale in any market, or that any new indications will be approved for any existing products in any market, or that any approvals which are obtained will be obtained at any particular time, or that any such products will achieve any particular revenue levels. Nor can there be any guarantee that the Group will be successful in its efforts to improve the quality standards at any or all of our manufacturing sites, or that we will succeed in restoring or maintaining production at any particular sites. Neither can there be any guarantee that the Group, or any of its divisions, will achieve any particular financial results, either in the near-term or in the long-term. In particular, management's expectations could be affected by, among other things, unexpected regulatory actions or delays or government regulation generally; unexpected clinical trial results, including additional analyses of existing clinical data or unexpected new clinical data; the Group's ability to obtain or maintain patent or other proprietary intellectual property protection, including the ultimate extent of the impact on the Group of the loss of patent protection on key products which commenced last year and will continue this year; unexpected product manufacturing and quality issues, including the potential outcomes of our efforts at the Sandoz and Alcon sites that are subject to Warning Letters, and with respect to our efforts to restart production of products formerly produced at the Consumer Health manufacturing facility at Lincoln, Nebraska; government, industry, and general public pricing pressures; uncertainties regarding actual or potential legal proceedings, including, among others, actual or potential product liability litigation, litigation and investigations regarding sales and marketing practices, shareholder litigation, government investigations and intellectual property disputes; competition in general; uncertainties regarding the effects of the ongoing global financial and economic crisis, including the financial troubles in certain Eurozone countries; uncertainties regarding future global exchange rates; uncertainties regarding future demand for our products; uncertainties necessarily involved in long-term financial projections; uncertainties involved in the development of new healthcare products; the impact that the foregoing factors could have on the values attributed to the Group's assets and liabilities as recorded in the Group's consolidated balance sheet; and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those described herein as anticipated, believed, estimated or expected. Novartis is providing the information in this presentation as of this date and does not undertake any obligation to update any forward-looking statements as a result of new information, future events or otherwise. 2 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Table of Contents  Key Principles of Biosimilar development • What is a Biosimiliar? • Differences to Generic Medicines • Development via a Two-Step Procedure  Overview of international Guidance on Biosimilars  Novartis Position on Biosimilars  Summary and Regulatory Needs 3 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Table of Contents  Key Principles of Biosimilar development • What is a Biosimiliar? • Differences to Generic Medicines • Development via a Two-Step Procedure  Overview of international Guidance on Biosimilars  Novartis Position on Biosimilars  Summary and Regulatory Needs 4 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Different types of biologics in circulation Not every version of a biologic is a biosimilar Noncomparable Counterfeit medicine Originator Biosimilar • First registration of new molecule • Version of registered original biologic • Questionable copy of registered original biologic • Illegal copy version of registered original biologic • Approval based on extensive comparability exercise via special and stringent registration pathway (e.g. in EU) • Approval not based on demonstrated comparability without special registration pathway; sometimes standalone application • Biological and pharmaceutical quality unclear, mostly substandard or even harmful • Patients can expect same clinical profile as with originator • Patients cannot expect the same clinical profile as with originator • Approval based on demonstrated quality, safety and efficacy 5 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Different types of biologics in circulation Not every version of a biologic is a biosimilar Noncomparable Counterfeit medicine Originator Biosimilar • First registration of new molecule • Version of registered original biologic • Questionable copy of registered original biologic • Illegal copy version of registered original biologic • Approval based on extensive comparability exercise via special and stringent registration pathway (e.g. in EU, USA, Canada, Australia) • Approval not based on demonstrated comparability without special registration pathway; sometimes standalone application • Biological and pharmaceutical quality unclear, mostly substandard or even harmful • Approval based on demonstrated quality, safety and efficacy • Patients can expect same clinical profile as with originator • Patients cannot expect the same clinical profile as with originator 6 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • What is a Biosimilar? Definition proposed by EMA in draft guideline on „similar biological medicinal products‟1:  A biosimilar is a biological medicinal product containing a version of the active substance of an already authorised original biological medicinal product (reference medicinal product).  A biosimilar demonstrates similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise. 1 http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2013/05/WC500142978.pdf 7 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Differences between Generics and Biosimilars Small molecules Expiry of patent and other exclusivities Biosimilars Generics  Same qualitative and quantitative composition in active substances and the same pharmaceutical form as the referenced originator product  Abbreviated dossier: own quality information, demonstrated bioequivalence as well as referring to the established safety and efficacy data of the reference product  Generics and reference product are usually interchangable/substitutable Original biologics  A version of the active substance of an already authorized original biological medicinal product  Demonstrates similarity to the reference product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise  Patients can expect the same clinical outcomes from a biosimilar and the originator drug 8 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Development of high-quality biosimilars is a systematic and robust process with two key steps Step 1 Step 2 Develop highly similar product Drug substance Formulation / Drug product Technical development to achieve a “highly similar” molecule, which matches the quality attributes of the reference product Demonstration of structural and functional similarity Confirm biosimilarity GLP Tox. Phase I Phase III Process validation Targeted non-clinical and clinical program to demonstrate similarity Scope depends on similarity in quality attributes and requires agreement with health authorities 9 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Step 1: Variability of the reference product defines the target Biological Activity (Units/mg) Biologic products vary from batch to batch • Non-identicality is a normal principle in glycosylated proteins • No batch of any biologic is “identical” to the other batches • Low variability is natural and generally not problematic for clinical outcome Manufacturing changes lead to more pronounced shifts • Manufacturing changes are made frequently • Changes in the manufacturing process generate slightly different versions of the originator molecule • These shifts usually have no implication for clinical function Batch of drug substance (DS) Schneider, C. K.: Biosimilarity: A better definition of terms and concepts. 25th Annual DIA EuroMeeting, 04-06/03/2013, Amsterdam 140 ADCC Potency [% of reference] 2,0 Unfucosylated G0 [% of glycans] PostShift 1,6 120 PostShift 100 80 12.2008 0,8 Pre-Shift 0,4 Pre-Shift 60 08.2007 1,2 05.2010 Expiry Date 09.2011 0,0 08.2007 12.2008 05.2010 09.2011 Expiry Date Schiestl, M., et al.: Acceptable Changes in Quality Attributes of Glycosylated Biopharmaceuticals. Nature Biotechnology, 29 (4): 310-312, 2011 10 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Biosimilars are approved biologics with comparable Q, S and E to a reference product Approved biosimilar in EU What is a biosimilar? NO difference to originator • Developed and manufactured using state-of-theart technology • Demonstrated comparable quality (Q), safety (S), and efficacy (E) to a reference product • Approved via stringent regulatory pathways Sample 1 2 3 4 Brockmeyer C & Seidl A et al. Eur J Hosp Pharm Pract 2009;15:34–40 What is NOT a biosimilar? Non-comparable “copy biologic” ≠ biosimilar • Non-comparable or alternative copy biologics are NOT biosimilars NOT similar to Reference E • Have not demonstrated biosimilarity via a stateof-the-art comparability exercise • Not approved following a specific biosimilars registration pathway (e.g. in line with WHO recommendations) Sample E IA IB IIA IIB IIIA IIIB IV 11 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only V VII VIII E Schellekens H et al. Eur J Hosp Pharm Pract 2004;3:43–7
    • Step 2: Demonstration that no meaningful difference in clinical profile can be expected  Targeted non-clinical and clinical program with indication and endpoints most sensitive to detect differences; no re-demonstration of safety and efficacy  Extrapolation to other indications of the reference product should be possibile and justified based on the “Totality-of-Evidence”, including: • High level of structural (as demonstrated by physicochemical characterization) and functional (as demonstrated by in vitro biological assays) similarity • Similarity regarding pharmacokinetics in humans • Similar efficacy and safety in a single, most sensitive indication (immunogenicity) • Same mode-of-action of indications (if known)  Immunogenicity data should be always required for all biologics, including biosimilars  Risk management plans for post-licensing surveillance should be routinely required for all new drugs, including biosimilars 12 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Illustration of the difference between originator and biosimilar development Originator development Biosimilar development Additional clinical studies Clinical studies PK/PD Non-clinical The world turned upside down.... Analytical PK/PD Non-clinical Analytical Comparison with the reference product  Main focus of the originator development program is on clinical studies; for the biosimilars on the analytical studies  The purpose of the clinical program of the biosimilar is to confirm similarity of efficacy and safety to the reference product, not to re-establish efficacy and safety  Therefore, design and endpoints of the clinical studies conducted with the biosimilar are different Source: modified slide shown by EGA at EMA Workshop in London on 31 Oct 2013
    • Table of Contents  Key Principles of Biosimilar development • What is a Biosimiliar? • Differences to Generic Medicines • Development via a Two-Step Procedure  Overview of international Guidance on Biosimilars  Novartis Position on Biosimilars  Summary and Regulatory Needs 14 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • WHO – 2009 Guidelines on evaluation of similar biotherapeutic products (SBPs)  Provides globally acceptable principles1 for licensing of biotherapeutic products that are claimed to be similar to original biotherapeutic products: • “A SBP is intended to be similar to a licensed biotherapeutic product for which there is a substantial evidence of safety and efficacy. The ability for the SBP to be authorized based on reduced non-clinical and clinical data depends on proof of its similarity to an appropriate RBP through the comparability exercise.” • “Comprehensive characterization and comparison at the quality level are the basis for possible data reduction in the non-clinical and clinical development.” • “Significant differences between the SBP and the chosen RBP detected during the comparability exercise would be an indication that the products are not similar and more extensive non-clinical and clinical data may be required to support the application for licensing.” 1 http://www.who.int/biologicals/areas/biological_therapeutics/BIOTHERAPEUTICS_FOR_WEB_22APRIL2010.pdf 15 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • European Medicines Agency: Well-established regulatory framework for biosimilars (2005)  Legal basis • Directive 2001/83/EC as amended, Art 10(4) • Multiple general and product specific guidelines that are regularly updated (refer to next slide)  Main principles • Regulatory pathway structured like the process to approve originators after significant manufacturing change • Two-step approach to demonstrate similarity to reference product • Extrapolation across indications possible under justified conditions • Use of non-European reference product for partial demonstration of similarity based on bridging studies • Acceptance of same INN and a label that allows the healthcare professional to make a treatment decision • No statement on interchangeability/substitutability; competence with the national governments 16 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • European Medicines Agency EU Guidelines for Biosimilars General General Biosimilar Brochure Product-specific Other Somatropin Statistical methods for comparability in quality attributes* Epoetin Q&A Document “Overarching” G-CSF Insulin LMWH Quality Interferon alfa Non-clinical Risk Management Plan Interferon beta Clinical Immunogenicity assessment of biotech products Monoclonal Antibodies Follicle Stimulation Hormone G-CSF: Granulocyte-colony stimulating factor (filgrastim or lenograstim); LMWH: Low Molecular Weight Heparin; *Concept paper 17 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • US Food and Drug Administration  Legal basis • Patient Protection and Affordable Care Act (Affordable Care Act), of 2010 • Biologics Price Competition and Innovation Act (BPCI Act) creates an abbreviated licensure pathway for biological products that are demonstrated to be “biosimilar” to or “interchangeable” with an FDA-licensed biological product • A number of (draft) guidance documents1  Main principles • Licensed biosimilar and interchangeable biological products will have to meet the Agency‟s exacting standards of safety and efficacy • Risk-based “totality-of-the-evidence” approach in support of a determination of biosimilarity of the proposed product to the reference product via a stepwise approach in the development of biosimilar products • Distinction of „biosimilar products‟ and „interchangeable biosimilar products‟ 1 http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologic Applications/Biosimilars/ 18 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Table of Contents  Key Principles of Biosimilar development • What is a Biosimiliar? • Differences to Generic Medicines • Development via a Two-Step Procedure  Overview of international Guidance on Biosimilars  Novartis Position on Biosimilars  Summary and Regulatory Needs 19 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Novartis develops both, innovative medicines and biosimilars of high quality Environment Patient needs Novartis portfolio Pharmaceuticals Innovative Medicines Innovative medicines Alcon (Eye care) Sandoz Prevention (Generics) Full range of healthcare options OTC Affordable options Animal Health Self-care Vaccines and Diagnostics 20 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only Generics and Biosimilars
    • Novartis Position on Biosimilars – Principles 1-4 Biosimilars are biologics Step-wise development of biosimilars Biosimilars should be subject to the same requirements as any other biologics of the same class Biosimilar development programs should follow step-wise approach and be scientifically sound Extrapolation of indication possible Extrapolation of indication should be allowed if scientifically justified, i.e. if „totality-of-evidence‟ has been demonstrated Interchangeability A biosimilar that has been registered via a robust regulatory pathway has demonstrated to have the same clinical profile as the reference product For details please refer to: http://www.novartis.com/downloads/corporate-responsibility/resources/positions/biosimilars-science-basedapproval-sustainable-market-access.pdf 21 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Novartis Position on Biosimilars – Principles 5-8 Same INN for biosimilars Biosimilar and reference product should have the same INN if the molecular characteristics of the biosimilar are within the reference product‟s range of variability and comparable safety and efficacy have been shown Same pharmacovigilance for biosimilars Robust and adequate pharmacovigilance measures needed for all medicinal products based on their individual risk profile High registration standards for biosimilars Local approval requirements need to ensure high standards of comparability between reference and biosimilar products Fair competition in the market Novartis supports both, the promotion of innovation and the possibility of fair competition by biosimilar products following loss of exclusivity For details please refer to: http://www.novartis.com/downloads/corporate-responsibility/resources/positions/biosimilars-science-basedapproval-sustainable-market-access.pdf 22 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Table of Contents  Key Principles of Biosimilar development • What is a Biosimiliar? • Differences to Generic Medicines • Development via a Two-Step Procedure  Overview of international Guidance on Biosimilars  Novartis Position on Biosimilars  Summary and Regulatory Needs 23 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Summary – Biosimilars...  ... are successors to a biologic medicine that has been marketed based on a full registration dossier and has lost its exclusivity  ... are not simple generics due to their complexity in terms of size, structure and manufacturing and therefore require a specific registration pathway  ... have demonstrated similarity to the reference product via a twostep comparability procedure: a. Analytical investigation to demonstrate structural and functional similarity b. Targeted non-clinical and clinical trials to confirm similarity - de novo proof of efficacy not necessary 24 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Biosimilars should be approved according to specific, highly stringent regulations  High-quality biosimilars are safe treatment options and have the same issues as all other biologics, but do not generate more concerns  The quality standards for biosimilars should be the same as for original biologics  Biosimilars should be evaluated according to rigorous guidelines1, and must have • Highly comparable structural and functional attributes • No clinically relevant differences  Products that do not meet these high standards for similar biological products should not be approved and not put in circulation  A robust pharmacovigilance system should be in place to support patient safety with all medicinal products 1 Refer to guidance from WHO, EMA and/or FDA 25 | Workshop on Biotherapeutics & Biosimilar Medicines - 19 Nov 2013 | K Heidenreich | Business Use Only
    • Thank you!