Biosimilar Labelling Workshop

Tuesday 2 February 2016 Park Inn by Radisson, Brussels Words of welcome by EBE and EuropaBio

Barbara Freischem, Executive Director EBE Miriam Gargesi, EuropaBio Healthcare Director EuropaBio – who we are

.Since 1996, EuropaBio, the European Association for BioIndustries, brings together bioscience companies from all fields of R&D, testing, manufacturing and distribution of biotechnology products .We represent more than 60 corporate members, 15 associate members and BioRegions .Through our 17 National Associations, we are the voice of over 1800 small- and medium- sized enterprises in Europe EuropaBio – what we stand for

.New products that help society as a whole to have better, longer, healthier and greener lives .Highest ethical behaviour and transparency based on a foundation of responsible innovation and sound science for all. All our members adhere to our Core Ethical Values. .Openness to dialogue, with a focus on developing Public Private Partnerships and providing ideas and solutions to decision makers .Breakthroughs in R&D in key strategic fields to satisfy unmet societal needs for future generations .A positive view of biotechnology in the eyes of the public and decision-makers .A free market where innovation can thrive EuropaBio – we represent 3 industry sectors EBE – who are we EBE vision & mission EBE – Partner of choice for biopharma

EBE brings together 500 experts in biotech 500 product development

52 Companies representing companies of 52 all sizes ( 60 % of them SME - Mid Cap ) EBE is the Europe’s expert voice for emerging bioscience & technology and the leading platform for the health innovation C C-level strategy setting board ecosystem. Level

We provide an active forum for stakeholder Financially self-sufficient and sustainable engagement where emerging knowledge and expertise meets and prepares the regulatory and entrepreneurial policies and Benefits from strong collaboration with key stakeholders EMA – (CAT, BWP, BMWP) EC, Investors, EIB, EIF, Patient conditions to accelerate therapeutic Organisations, Medical Societies and national biotech innovations to patients. associations About the biopharmaceutical industry European Biopharmaceutical Enterprises Members EuropaBio Healthcare members Biopharmaceutical Companies

National Biotech Associations

Associate Members: Academia, Healthcare Industry Service Providers & Investors Any questions?

Barbara Freischem Miriam Gargesi Executive Director Director, Healthcare Biotechnology Tel.: +32 2 626 2564 Tel. +32 2 7391183 Email: [email protected] Email: [email protected]

European Biopharmaceutical Enterprises EuropaBio Rue du Trône 108 Avenue de l’armée 6 Leopold Plaza Building B-1040 Brussels B-1050 Brussels, Belgium www.europabio.org T: +32 2 626 25 55 www.ebe-biopharma.eu

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Catherine Akers, EBE & EuropaBio Contents

1. Introduction to biologics (including biosimilars)

2. Manufacturing of biologics (including biosimilars)

3. Biosimilar development pathways

4. Biosimilars approved to date

5. Key considerations post-approval -Extrapolation -Traceability -Switching INTRODUCTION TO BIOLOGICS (INCLUDING BIOSIMILARS) What is a Biological Medicinal Product?

Definition

Biologic Medicinal Products or biologics, are medical products manufactured from a variety of natural sources (human, animal or microorganism). Like small molecule drugs, biologics are intended to treat diseases and medical conditions. Other biologics are used to prevent or diagnose diseases. Biologics are Larger and Structurally More Complex than Small Molecule Drugs

Acetyl salicylic acid1 ~180 daltons Insulin2 21 atoms 51 amino-acids ~6,000 daltons 788 atoms Human Growth Hormone3 191 amino-acids ~22,000 daltons 3091 atoms

Images not to scale. Image Source: www.jtbaker.com, http://www.umass.edu/microbio/chime/antibody/abquests.htm 1. Aspirin comprehensive prescribing information. www.fda.gov/ohrms/dockets/ac/03/briefing/4012B1_03_Appd%201-Professional%20Labeling.pdf. 2. Insulin product information. 1999. www.sigmaaldrich.com/etc/medialib/docs/Sigma/Product_Information_Sheet/ 2/i2767pis.Par.0001.File.tmp/i2767pis.pdf. IgG1 antibody4 3. Johns Hopkins University. *139250 Growth hormone 1:GH. OMIM website. omim.org/entry/ 139250. >1000 amino-acids Accessed Jan 24, 2013; 4. Davies DR, Padlan EA. Three-dimensional structure of immunoglobulins. Ann Rev Biochem. 1975;44:639- ~150,000 daltons 667. >20000 atoms Biologics Are Different From Small Molecules

Small Molecules and Generics Biologics and Biosimilars

Acetylsalicylic acid1 Monoclonal antibody Example MW = ~ 180 Da MW = ~ 150,000 Da5

Size Small2 Large2

Complex with many options for post- Structure Simple3 and well-defined2 translational modifications6 Each biosimilar is manufactured Predictable chemical process; using a unique cell line2; complex Manufacturing identical copy can be made2 manufacturing; expected to be highly similar but not identical2

Properties Difficult to fully characterize due to a Characterizations Easy to fully characterize4 mixture of related molecules4 Sensitive to storage and handling Stability Relatively stable2 conditions2 Risk of Low2 High2 immunogenicity

1. Aspirin (acetylsalicylic acid) prescribing information, Bayer. 2. Genazzani AA, et al. BioDrugs. 2007;21:351-356. 3. Prugnaud JL. Br J Clin Pharmacol. 2008;65:619-620. 4. Gottlieb S. Am J Health Syst Pharm. 2008;65(14 suppl 6):S2-S8. 5. MW, molecular weight. Lipman NS, et al. ILAR J. 2005;46:258-268. 6. Roger SD. Nephrology (Carlton). 2006;11:341-346. MANUFACTURING OF BIOLOGICS (INCLUDING BIOSIMILARS) Biologics (including biosimilars) Are Made by Living Cells Through Well-Controlled Processes A typical biotechnology manufacturing process includes multiple stages

Transfection of Patient 1 DNA into host cell treatment2

Cell line 2 selection and Refrigeration, 2 development1 storage, and transport1

Manufacturer establishes a unique master cell Formulation,1 bank1 fill,2 and finish2

Cell culture Characterization and expansion1 and stability2

Isolation2 and purification1 1. Kresse GB. Eur J Pharm Biopharm. 2009;72:479-486. 2. Sharma BG. EJHP Practice. 2007;13:54-56. What are biosimilars? • A biosimilar is a biological medicinal product that contains a version of the active substance of an already authorised original biological medicinal product (reference medicinal product) in the EEA. Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive comparability exercise needs to be established.1 • Whereas producing generic versions of off-patent chemically-synthesized medicines is relatively easy, producing a biosimilar is far more complicated due to the complex molecular structure and the unique manufacturing process required for biological medicines • The use of similarity exercises is part of the unique pathway needed to appropriately assess biosimilars to ensure they are comparable to the reference product.

1 Guideline on Similar Biological Medicinal Products, CHMP/437/04 Rev 1, 23 October 2014

10 Conclusion on biologics (including biosimilars)

• Each biologic (including biosimilar) is unique due to its individual manufacturing process (different cell line, specific operating conditions, different methods, reagents and reference standards etc.)

• Natural variability is a key feature of all biologics

• Biologics are large molecules which are fragile in nature and susceptible to change

• Biosimilars are designed to be similar but not identical to their reference product based on a comprehensive comparability exercise BIOSIMILAR DEVELOPMENT PATHWAYS Biosimilar Pathways Are Being Established Worldwide 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015

Guideline EU development EU TUR KOR USA CUB CRI JOR COL CHN Legal Overarching Pathway Guidelines

MYS JPN CAN ARG NGA UKR CHL MEX

The EMA published the first biosimilar regulatory approval pathway for the TWN SIN BRA PER MDA PHL URY EU member states

AUS WHO SAU THA

ISR GTM EGY

KAZ IRI

VEN The flag locations reflect Amgen’s best judgment of the effective dates for the pivotal implementing laws, regulations, or guidelines for reviewing a biosimilar application; information is current as of February 19, 2015. ZAF EMA, European Medicines Agency; EU, European Union.

Sources: Publicly available information from national regulatory authorities and World Health IND Organization guidelines and data on file. EMA guidelines are responding to the evolving understanding and challenges

Defines Overarching Guideline (CHMP/437/04 Rev 1) Principles ‘Guideline on Similar Biological Medicinal Products’

General Overarching Non Clinical/Clinical Overarching Quality Guidelines Guideline (EMEA/CHMP/BMWP/42832/2005 Rev.1) Guideline on Q/S/E (EMA/CHMP/BWP/247713/2012)

Class specific guidance: non clinical/clinical aspects

Insulin Somotropin GCSF Epoetins INF-α LMWH mAbs INF - β Folliotropin

2015 2006 2006 2010 2009 2013 2012 2013 2013

Under Under consultation consultation

Reproduced from DIA Applying the EU biosimilar concept

Totality of Evidence/Stepwise Approach

Biosimilar?

Clinical Originator Biosimilar

Non clinical Biosimilar? in vitro testing Quality (+specific in vivo if needed Non-Clinical Cross reference Clinical Cross Foundation- Quality reference comparison, functional Biosimilar? Cross reference – Integrated Biosimilarity Exercise – aspects eg binding class specific Safety and Efficacy Quality, Safety and Efficacy

24 Comparative Clinical Safety and Efficacy Assessments Are Needed to Address Residual Clinical Studies (Safety, Uncertainties 1 Factors that affect the type and extent of Efficacy) clinical efficacy and safety studies needed2 Clinical •Nature and complexity of the reference Pharm. •Mechanism of action of reference and (PK/PD) disease pathology •Extent of clinical experience with the reference and its therapeutic class Nonclinical •Extent to which differences in structure and function studies predict differences in clinical outcomes •Extent to which PK and PD studies Analytical predict clinical outcomes (eg, are Characterization (Structure sensitive PD markers available) & Function Assessment)

1. Kozlowski S. Presented at: Biotechnology Technology Summit; June 13, 2014; Rockville, MD. https://www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski%20-%20Biomanufacturing%20Summit.pdf. Accessed February 5, 2015. 2. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February PD, pharmacodynamics; PK, pharmacokinetics. 7, 2015. Immunogenicity Studies Are Critical for Establishing Biosimilarity

Safety, Efficacy, and Clinical Immunogenicity Studies One clinical study in • The goal of immunogenicity studies is to a sensitive population to inform establish that there are no clinically immunogenicity1 meaningful differences in incidence and Clinical severity of human immune response Pharm. PK/PD between the biosimilar and reference product2

• Immunogenicity can be tested during clinical safety and efficacy studies, including PK/PD studies1 • Studies should be conducted in sensitive population2 • Studies should include assessment of binding and neutralizing antibodies2 PD, pharmacodynamics; PK, pharmacokinetics. 1. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015. 2. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015. BIOSIMILARS APPROVED TO DATE EU Began Approving Biosimilars in 20061; More Recently, mAb Biosimilars Have Also Been Epoetin alfa Epoetin alfa Approved FDA Epoetin alfa 2 Filgrastim approval Epoetin zeta Infliximab Filgrastim Epoetin zeta Infliximab Filgrastim

2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

Somatropin Filgrastim Filgrastim Filgrastim Insulin Etanercept

Filgrastim Follitropin α Filgrastim Filgrastim Follitropin α

Many of the approved biosimilars in Europe are based on recombinant versions of naturally occurring hormones and cytokines3

Given the approaching patent expiration of multiple biologics in the next five years,4 several biosimilars are in development throughout the world

ESA, erythropoiesis-stimulating agent; EU, European Union; FDA, Food and Drug Administration; FSH, follicle-stimulating hormone; G-CSF, granulocyte colony-stimulating factor; GH1, human growth hormone; mAb, monoclonal antibody; SA, short-acting; TNF, tumor necrosis factor. Each box represents a unique manufacturer. 1. EMA. European Public Assessment Reports for Human Medicines. http://www.ema.europa.eu/ema/index.jsp?curl=pages%2Fmedicines%2Flanding%2Fepar_search.jsp&mid=WC0b01ac058001d124&searchTab=searchByAuthType&alreadyLoaded=true&isNewQuery=tru e&status=Authorised&keyword=Enter+keywords&searchType=name&taxonomyPath=&treeNumber=&searchGenericType=biosimilars&genericsKeywordSearch=Submit. Accessed March 3, 2015. 2. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.DrugDetails. Accessed March 12, 2015. 3. Schellekens H. NDT Plus. 2009;2(suppl 1):i27-i36. 4. GaBIonline. http://www.gabionline.net/Biosimilars/Research/US-54-billion-worth-of-biosimilar-patents-expiring-before-2020. Accessed February 16, 2015. BIOSIMILARS – KEY CONSIDERATIONS 1. EXTRAPOLATION Extrapolation

• The decision whether to extend the efficacy and safety data from an indication (a medical condition, disorder or disease) for which the biosimilar has been clinically tested to other conditions for which the branded product is approved, is know as ‘extrapolation’.

European Commission Consensus Information Paper 2013, What you need to know about biosimilar medicinal products. In Addition to Totality of Evidence, Extrapolation of Indications Requires Scientific Justification A proposed biosimilar product may be licensed in one or more additional conditions of use for which the reference product is licensed, if appropriate scientific justification is provided Scientific Justification Should Establish

Any other factor PK, PD, and Immunogenicity Differences in that may affect MOA in each biodistribution of the product expected safety or condition in different in different toxicities in effectiveness in of usea patient patient each condition each condition populations populations of use of use

MOA, mechanism of action; PD, pharmacodynamics; PK, pharmacokinetics. aMOA in each condition of use may include target/receptors for each relevant activity/function; binding, dose/concentration of response, and pattern of molecular signaling upon engagement of target; relationship between product structure and target/receptor interactions; and location and expression of target/receptors. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed April 30, 2015. BIOSIMILARS – KEY CONSIDERATIONS 2. TRACEABILITY Ongoing Pharmacovigilance Is Important for Biologics and Biosimilars Robust post-marketing safety monitoring is important to ensure similar safety and effectiveness between the biosimilar and the reference drug

Safety monitoring should take into account the safety or effectiveness concerns associated with reference product

Safety monitoring should have the ability to differentiate between adverse events associated with the proposed biosimilar product vs those associated with the reference drug or other biosimilars

FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015. Multiple products creates challenges for PV Brand names vs. INNs 1998 2001 2009

. Eprex® (epoetin alfa) . Eprex® (epoetin alfa)  Eprex® (epoetin alfa) . NeoRecormon (epoetin beta) . NeoRecormon (epoetin beta)  NeoRecormon (epoetin beta) . Aranesp® (darbepoetin alfa)*  Aranesp® (darbepoetin alfa)*  Dynepo® (epoetin delta) (withdrawn)  Mircera® (peg-epoetin beta)  Ratioepo (epoetin theta) Directive 2010/84/EU Article  Biopoin (epoetin theta) • Binocrit™ (epoetin alfa) Member States 102(e) states that: • Abseamed (epoetin alfa) must ensure, where necessary through the • Epoetin alfa Hexal (epoetin alfa) follow-up of suspected adverse reaction o reports, that all appropriate measures are  = Full marketing authorization Silapo (epoetin zeta) taken to identify clearly any biological • = Biosimilar authorization #1 (Aug 2007) o Retacrit® (epoetin zeta) medicinal product prescribed, dispensed, or o = Biosimilar authorization #2 (Dec 2007) sold in their territory which is the subject of a suspected adverse reaction report, with due According to The United States Patent and Trademark Office’s on-line search tool at regard to the name of the medicinal product http://www.uspto.gov/ and accessed on June 29, 2011, the following marks are registered or otherwise listed with that office: in accordance with Article 1(20), and the Aranesp® is a registered trademark of Amgen, Inc. batch number;’ Mircera® is a registered trademark of Hoffmann-La Roche Inc. CORPORATION NEW JERSEY Dynepo® is a registered trademark of Aventis Pharma Holding GmbH CORPORATION FED REP GERMANY The following list of marks may be registered with jurisdictions outside of the United States: NeoRecormon, Biopoin, and Ratioepo

Some products are marketed in different jurisdictions under different brand names. Data Source: European Public Assessment Reports published on EMA Website. Available at http://www.ema.europa.eu/pdfs/human/press/pr/4031706en.pdf Withdrawal statement for Epoetin Delta available at http://www.ema.europa.eu/humandocs/PDFs/EPAR/dynepo/12666909en.pdf ** Morrison A, Walker C, Fox A. PharmacoVigilance Review. 2009;3(4):12-14. Traceability for biological products: The need to ensure no disconnects between prescribing, dispensing and adverse event (AE) reporting AE Report AE Report

Prescription by brand Prescription by INN

In the event patient In the event patient experiences an AE, Pharmacist dispenses per Pharmacist dispenses an experiences an AE, reporter knows physician stated brand or available or least reporter may not exactly which brand contacts physician to agree expensive biological with have immediate the patient was change same INN access to the precise dispensed brand dispensed to the patient

12 BIOSIMILARS – KEY CONSIDERATIONS 3. INTERCHANGEABILITY AND SWITCHING Interchangeability • EU definition • The medical practice of changing one medicine for another that is expected to achieve the same clinical effect in a given clinical setting and in any patient on the initiative, or with the agreement of the prescriber. • European Commission Consensus Information Paper 2013, What you need to know about biosimilar medicinal products.

• US definition • ‘The term ‘interchangeable’ or ‘interchangeability’, in reference to a biological product is shown to meet the standards described in subsection (k)(4), means that the biological product may be substituted for the reference product without the intervention of the health care provider who prescribed the reference product.’ • PHS Act § 351(i)(3), 42 USC § 262(i)(3) Switching

• EU Definition • [Switching is] the decision by the treating physician to exchange one medicine for another medicine with the same therapeutic intent in patients who are undergoing treatment • European Commission Consensus Information Paper 2013, What you need to know about biosimilar medicinal products Summary: Pillars of Biosimilar Development EMA recommends a step-wise approach for demonstration of biosimilarity and considers the “totality of evidence”

Physiochemical and functional characterization of both the reference and the biosimilar is a foundational step in biosimilars development

Comparative human PK and PD studies demonstrating absence of clinically meaningful differences between reference and biosimilar are critical to establishing biosimilarity

Immunogenicity testing demonstrating no clinically meaningful differences in incidence and severity is required

It is likely that at least one clinical study in a sensitive population is needed to confirm safety and efficacy and inform immunogenicity

Ongoing safety monitoring is critical to ensuring patient safety Biosimilars Product Labelling

Keith Watson, EBE & EuropaBio Outline of presentation

• Introduction to EU product labelling

– SmPC and package Leaflet

• Possible scenarios for the label of a biosimilar

• Variability and evolution of labels for biosimilars in Europe

• Snapshot of global biosimilar labelling (US, Canada, Japan)

• EBE and EuropaBio positions on labelling

• EU physician survey on SmPC preferences for biosimilars

41 EMA presentation on basics of the SmPC

Now present a short video from EMA website outlining basics of the SmPC http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/document_listing/ document_listing_000357.jsp&mid=WC0b01ac05806361e1

42 The SmPC – background (1/2)

1. Summary of Product Characteristics (SmPc) is a key part of the marketing authorisation of all medicines authorised in the EU 2. Basis of information for healthcare professionals on how to use a medicine safely and effectively. 3. Kept updated throughout the lifecycle of a medicine as new efficacy or safety data emerge. 4. SmPC is the basis for the preparation of package leaflets, so are important documents in enabling information on medicines to reach patients.

Source: EMA homepage – human regulatory – product information (link) 43 The SmPC – background (2/2)

• Required detail in the SmPC described in EMA guidelines; NO specific biosimilar labelling guideline. – QRD guidance groups biosimilars alongside generics and hybrid products and allows mention of specific information on the biosimilar where justified.

• 19 Biosimilar products approved in the EU to date – Variable SmPCs relating to mention of clinical information on the biosimilar or only the reference product

44 Legal basis for the package leaflet (PL)

Directive 2001/83/EC: • ● The inclusion in the packaging of all medicinal products of a package leaflet (PL) shall be obligatory. (Art. 58)

• ● The PL must be written and designed to be clear and understandable, enabling the users to act appropriately, when necessary with the help of health care professionals. (Art 63.2) • ●It also defines the information which has to be included in the Package leaflet (Art. 59

45 Lifecycle of the package leaflet (PL)

• The PLs are drafted by the pharmaceutical companies based on their data

• ●After submission of the dossier, starts a number of rounds of review involving different actors: * Assessors from Member states * EMA * Patients

• ● Additional tool: User testing (performed during a procedure): Legal requirement since 2005 - Not only looking at the content but also at the design and lay-out of the leaflet

46 EU-Possible biosimilar labelling scenarios • Currently, Summary of Product Characteristics (SmPC) of an originator biologic and its biosimilar(s) are almost identical • In 2012, Schneider et al discussed 3 options for the content of a biosimilar SmPC which can be summarised as follows: – Product label is an identical copy of the reference label – Product label only gives information obtained with the biosimilar – Product label is a combination of information (for example, studies performed with the biosimilar and relevant safety and/or efficacy data from the reference product).

Schneider CK, Vleminckx C, Gravanis I, Ehmann F, Trouvin JH, Weise M, Thirstrup S. Setting the stage for biosimilar monoclonal antibodies. Nat Biotechnol. 2012 Dec;30(12):1179-85.

47 EU Biosimilar SmPCs – Example of variability

Tevagrastim- September 2008

Remsima - September 2013

48 EU Biosimilar SmPCs – What they all have

• Section 1: Name of Medicinal Product • Section 2: Qualitative and Quantitative Composition • Section 3: Pharmaceutical form • Section 5: Pharmacological Properties – Section 5.1: Pharmacodynamic Properties [brand name biosimilar] is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu

In case of Remsima, this is the only biosimilar specific information in the SmPC. For more info  EMA homepage  EPAR?

49 EU – Product labels of Biosimilar are identical to the originator

50 A combined approach: Label of the first biosimilar mAb (Remsima) approved in Canada

Health Canada issued a product monograph which has a combination of information of both the biosimilar and the reference product.

Adverse event section: Clinical Trial AEs described in the product mongraphare from Remsima studies, except for extrapolated indications, where data was taken from reference product studies. Also included, common AEs from both reference product and Remsima. Clinical trial section: Remsima studies presented Several Remsima / Remicade tables comparing PK data, efficacy, Immunogenicity and ADA results Also presented extensive table detailing in vitro activity between Remsima and Remicade

51 HC – Product labels of Biosimilar at least mention it is a SEB

52 A combined approach: Label of the first biosimilar mAb (Remsima) approved in Japan

• The label includes information on both the biosimilar and the reference product and a statement that the product is a biosimilar. • In parts of the label, the source (product) of the data is mentioned. • The pre-cautionary section includes a statement that caution should be exercised when switching from one biologic to another. • The ADR section consists of a combination of data from the reference product and the biosimilar. • The Pharmacokinetics and Clinical section include data from the comparative studies only and state that the data seen is equivalent with what is known for the reference product.

53 Swiss Medic Guidance

54 A generic approach: Label of the first Biosimilar (Zarxio) approved in US

 No mention of biosimilarity

Divergence from FDA’s draft guidance Diverge from FDA’s earlier draft guidance on “Scientific Considerations in Demonstrating Biosimilarity to a Reference Product”: "labelling of a proposed product should include all the information necessary for a health professional to make prescribing decisions, including a clear statement advising that: • This product is approved as biosimilar to a reference product for stated indication(s) and route of administration(s). • This product (has or has not) been determined to be interchangeable with the reference product."

 The latter was removed from the final FDA guidance (published in April)

55 EBE position on biosimilar labelling Key Messages – Published in Aug 2013

• The label should be a combination of information on both the biosimilar and the reference product (NO generic approach) • The combined approach allows transparent disclosure of all relevant information related to the biosimilar and the reference product – Transparency on the source of the data – Transparency on the basis for authorisation • Specific guidance for the labelling of biosimilars is of crucial importance • Prescribing requirements should be included in order to improve traceability and enhance pharmacovigilance. • Details should be further developed in consultation with the relevant stakeholders.

http://www.ebe-biopharma.eu/documents/59/22/EBE-position-paper-on-Biosimilars-Labelling

56 EuropaBio majority position on biosimilar labelling Key Messages – Published in Sep 2014 • A transparent label which combines information on both the biosimilar and the reference product. • The wording in the SmPC should clearly identify by name each product the data were generated with (e.g., the reference product, the biosimilar, or a larger class of products, where there is a class issue) • A brief discussion of the scientific justification for any extrapolation in the SmPC, an in-depth discussion should continue to be included in the European Public Assessment Record (EPAR). • European regulators to develop a specific guidance on the labelling of biosimilars and to no longer assign a generic label to biosimilars. • Details should be further developed in consultation with the relevant stakeholders.

http://www.europabio.org/positions/europabio-statement-labelling-biosimilars

57 EBE and EuropaBio recommend a combined approach (1/3)

Recommend a transparent biosimilar label that combines information on both the biosimilar and the reference product, in order to…. 1. Enable informed decisions by prescribers 2. Add value to EU healthcare – consistency and transparency for better understanding of biosimilars 3. Be fully in line with the distinct regulatory pathways established for biosimilar development, licensing and evaluation. 4. Recognize and reflect the information practices of prescribers – key role of the SmPC Specific biosimilar labelling guidance is of key importance and details of such guideline should be further developed in consultation with the relevant stakeholders.

58 Other stakeholders recommend a combined approach (2/3) • EBE and EuropaBio positions on labelling for biosimilars has consistently called for a tailored/combined approach to labelling – A “combined” model • Consistent with approaches in other regulatory authorities, some other stakeholders

http://gabi-journal.net/tell-me-the-whole-story-the-role-of-product-labelling-in-building-user-confidence-in- biosimilars-in-europe.html

http://www.worldpharmaceuticals.net/features/featurea-visible-difference-clinical-packaging-4627678/

59 Other stakeholders recommend a combined approach (3/3)

Physician’s Information Leaflet for biosimilar drugs shall be based only on the specific information available for the drug, and shall not be copied for the overall information provided in the leaflet of the original drug.

The Association of British Pharmaceutical Industry

60 Advantages of a combined approach

• Prescribers can see biosimilar data alongside that for the reference product, as this will explain the basis for approval (including indications, extrapolation) – as well as allow the prescriber to refer to the originator data to complete their understanding of the product • Allowing for characterisation data to be included to address the proof of biosimilarity – Assures the long-term safety profile for the reference product should be applied to biosimilar (including class warnings) as well • Transparent disclosure of all relevant information related to the biosimilar and the reference product – Transparency on the source of the data – Transparency on the basis for authorisation

61 Summary

• In Europe, there is no specific biosimilar labelling guidance which led to variable information in biosimilar labels so far (including a generic label for the recent Remsima approval).

• Labelling approaches taken differ across countries/regions, with Canada and Japan having been more transparent in their most recent biosimilar labels. • The position of EBE and Europabio members is -to recommend a combined biosimilar labelling approach -to have a consultation with all stakeholders

Effective and inclusive consultation has been a cornerstone of establishing trust and support for the EU biosimilar pathway.

62 EU Physician Survey on biosimilar labelling

• 25 minute online survey of 210 physicians in 7 countries representing 7 specialties • Physicians with at least 3 years of practice experience • Prepared by a multi-disciplinary team of regulatory affairs, public policy and scientific communication professionals in SFL (Solutions for Life Sciences*) • Review panel of medical doctors with backgrounds in clinical science, drug safety and as regulators • Key guiding principles: neutrality and transparency

*SFL Regulatory Affairs & Scientific Communications Ltd., Basel, Switzerland

63 Survey Design

PartPart 1:1: InformationInformation sourcessources PartPart 2:2: BiosimilarBiosimilar SmPCSmPC PhysiciansPhysicians’’ useuseofofinformationinformation Physicians’Physicians’ generalgeneral viewsviews sourcessources •• WhatWhat additionaladditional contentscontents areare helpful?helpful? •• WhichWhich,, whenwhenandandhowhow?? Physicians’Physicians’ preferencepreference forfor SmPCSmPC samplesample texts*texts* PhysiciansPhysicians’’ useuseofofthetheSmPCSmPC •• 33 samplessamples eacheach withwith 22 optionsoptions –– CurrentCurrent vsvs modifiedmodified SmPCSmPC •• WhenWhenandandhowhow?? –– SampleSampletextstexts bbasedased onon SmPCSmPC ofof BinocritBinocrit (a(a biosimilarbiosimilar epoetinepoetin alfa)alfa)

SmPC Sample 1 SmPCSmPC SampleSample 22 SmPCSmPCSampleSample 33 ‘5.1 Pharmacodynamic ‘4.2‘4.2 PosologyPosology andand methodmethod ofof ‘4.8‘4.8 UndesirableUndesirableeffectseffects’’ properties’ administration’administration’

* Selection of SmPC sections and sample texts based on assumptions about most interesting sections for physicians. For each sample of the different SmPC sections, physicians were shown: 1. A text excerpt from the current SmPC version, and asked to rate its helpfulness. 2. A modified version of the SmPC text excerpt with additional information, and asked to rate helpfulness of the additional information. 3. The current and the modified version of the SmPC section side by side, and asked which version they preferred.

64 Profile of participating physicians

Physicians were selected with a balanced geographical spread, and from key therapeutic areas where biologics are used

Country Specialty Experience with biologics

n (%) n (%) n (%) France 30 (14.3%) Dermatology 28 (13.3%) Originator(s) and 110 (52.4%) Germany 30 (14.3%) Endocrinology 28 (13.3%) biosimilar(s) Gastroenterology 28 (13.3%) Italy 30 (14.3%) Originator(s) only 64 (30.5%) Poland 30 (14.3%) Haematology 28 (13.3%) Biosimilar(s) only 14 (6.6%) Spain 30 (14.3%) Nephrology 35 (16.7%) Sweden 30 (14.3%) Oncology 28 (13.3%) None 22 (10.5%) UK 30 (14.3%) Rheumatology 35 (16.7%) Total 210 (100%) Total 210 (100%) Total 210 (100%)

43.3% of the participating physicians had experience of prescribing epoetin-alfa originator product

29.5% had experience prescribing epoetin-alfa biosimilars

65 IMPORTANT NOTE: Key results of the survey were presented at the meeting, however these slides have been omitted due to the results being submitted for publication, before which they cannot be distributed widely. Please contact us should you have any further questions at this point. EU physician survey – Conclusions

• The SmPC, together with professional guidelines and peer-reviewed publications, is the most frequently used source of information - The SmPC is an appropriate vehicle for information and guidance about the use of biological medicinal products including biosimilars - The SmPC section where clinical data and the biosimilar statement is currently placed (5.1) is not the main focus of physicians’ attention • The overwhelming majority of physicians prefer a biosimilar SmPC which includes biosimilar-specific information • The more specific the information is (i.e. which product, the biosimilar or the reference product, generated which clinical data), the more helpful it is considered by physicians

67 Similar findings from ASBM surveys

1. ASBM (Alliance for Safe Biologic Medicines) physicians’ survey on labelling in USA, 2015 http://safebiologics.org/resources/2015/03/new-asbm-survey-provides-physicians- views-on-biosimilar-labelling/

2. ASBM (Alliance for Safe Biologic Medicines) physicians’ survey in Europe, 2013

http://www.europabio.org/asbm-survey-european-prescribers-understanding-and- knowledge-biosimilar-medicines

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