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Biosimilars Knowledge Connect Slide Resource

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Introduction to biological medicinesand biosimilars

• A biosimilar is an approved version of a biological medicine with an identical primary amino acid sequence to the originator and developed with the intention to be as close to the originator as possible

• Like biological medicines, biosimilars are complex protein molecules that are produced by living organisms

• During the past 15 years, biological medicines have had a profound impact on healthcare>primarily in the areas of rheumatology and oncology>as well as endocrinology, cardiology, dermatology, gastroenterology, and neurology

• Many of the world’s top-selling medicines are now biological medicines• However, biological medicines are expensive (sometimes by several orders of

magnitude more than small-molecule chemical drugs), limiting patient access• As many biological medicines come off patent globally, there is great interest

in the development of biosimilars, which are likely to be more affordable

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The increasing rate of developmentof biosimilars

Patent expiries expected: 99

Patent expiries expected: 91

Patent expiries expected: 46

Biological medicines due to come off patent2,3

It has been estimated that 31 different companies were developing biosimilar monoclonal antibodies (as of March 2012), compared with 18 companies as of Sept 2011 – an increase of 67% in a 6-month period.1

1. Barkalow F, Biosimilar monoclonal antibodies. In the pipeline: major players and strategies. Citeline.2. Haag T (Lonza) and Krattiger C (GfK). The emergence of biosimilars—How are they different from generics

and what are the implications from marketing? EphMRA presentation. June 29, 2011.3. http://articles.chicagotribune.com/2012-08-13/news/sns-rt-elan-spinofftysabril6e8jd71t-20120813_1_tysabri-

elan-patent-protection

2010–2015 2016–2020 Post–2020

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As of Sept 2013, 16 biosimilars have been approved in the EU*

Biosimilar Sponsor Reference product Date of approval

Abseamed (epoetin alfa) Medice Arzneimittel Pütter (Germany) Eprex (Janssen) August 2007

Biograstim (filgrastim; G-CSF) CT Arzneimittel Neupogen (Amgen) September 2008

Binocrit (epoetin alfa) Sandoz (unit of Novartis) Eprex (Janssen) August 2007

Epoetin alfa Hexal (epoetin alfa) Hexal Biotech (owned by Novartis) Eprex/Erypo (Janssen) August 2007

Filgrastim Hexal (filgrastim; G-CSF) Hexal Biotech Neupogen (Amgen) February 2009

Nivestim (filgrastim; G-CSF) Hospira Enterprises Neupogen (Amgen) June 2010

Omnitrope (somatropin; human growth hormone) Sandoz Genotropin (Pfizer) April 2006

Ratiograstim (filgrastim; G-CSF) Ratiopharm (acquired by Teva)

Neupogen (Amgen) September 2008

Filgrastim Ratiopharm (filgrastim; G-CSF) Ratiopharm (acquired by Teva) Neupogen (Amgen) September 2008

(withdrawn April 2011**)

Retacrit (epoetin zeta) Hospira Eprex (Janssen) December 2007

Silapo (epoetin zeta) Stada Eprex (Janssen) December 2007

Tevagrastim (filgrastim; G-CSF) Teva Pharma Industries Neupogen (Amgen) September 2008

Valtropin (somatropin; HGH) BioPartners Gmbh Humatrope (Eli Lilly) April 2006

Zarzio (filgrastim; G-CSF) Sandoz (unit of Novartis) Neupogen (Amgen) February 2009

Inflectra (infliximab) Hospira Remicade (Janssen) 10 September 2013

Remsima (infliximab) Celltrion Remicade (Janssen) 10 September 2013

*Out of a total of 20 marketing authorization applications. **The marketing authorization for Filgrastim Ratiopharm was voluntarily withdrawn in 2011 at the request of the marketing authorization holder. Source:EMA biosimilar EPAR listing: Accessed October 2013.

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Even if a biosimilar uses the same human gene as its originator

It will differ in other partsof the process

Humangene DNA

vector

Cloning into DNA vector

Transfer intohost cell

Bacterial or mammalian cell produces protein

Fermentation

FormulationDifferent process = different product

Small-molecule generic Biosimilar

Low molecular weight and complexity High molecular weight and complex 3-D structure

Chemical synthesis Produced by living organisms

Manufacturing process easy to reverse-engineer Manufacturing process cannot be replicated

Identical copy of active ingredient

Although required to contain the sameprimary amino acid sequence, the biosimilaris not identical to the originator, but ratherhighly similar

Biosimilars differ from small-molecule generic drugs – manufacture

Adapted from The Biosimilars Handbook, Barclays Capital, 11 Feb 2011

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Biosimilars are subjected to a more rigorous clinical development process than generics

Biosimilars

Generics• Proof of quality and bioequivalence• No substantial clinical data required• Reference to originator’s data

• Different manufacturing processes can and often do yield differences in the end product

• After the quality of a biological medicine is demonstrated, some non-clinical and clinical studies are necessary

• Immunogenic response cannot be predicted and therefore must be tested

Source: J. Mascaro: Regulatory evaluation of therapeutic biological medicines, Aug 15, 2007

Small molecule

Biological medicine

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The potential impact of biosimilars

• A survey conducted in the European Union in 2010 found cost savings in 24 member states where biosimilars were marketed alongside their originators*>There was sustained price discounting in all countries, although this did vary at the

country level>Values range from a 5% discount for filgrastim in the UK to a 53% discount for the

same medicine in Denmark in 2009 >The availability of biosimilars of somatropin, epoetin alfa, and filgrastim in Europe

has led to price discounts relative to their respective originators ranging from 5–82%>The table below describes the mean price discount of biosimilar versions of the

medicines listed relative to their originator products

Expected cost savings

Mean discount in 24 EU member states 2007 2008 2009

Somatropin 25.4% 25.9% 14.1%

Epoetin 32.1% 17.3% 17.0%

Filgrastim ‐‐‐ 10.8% 35.0%

*Rovira J, Espín J, García L, and Olry de Labry A. The impact of biosimilars’ entry in the EU market. 2011. http://ec.europa.eu/enterprise/sectors/healthcare/files/docs/biosimilars_market_012011_en.pdf.

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Adapted with permission from Macmillan Publishers Ltd: Clin Pharmacol Ther (McCamish M and Woollett G. The state of the art in the development of biosimilars. 91(3):405–417), © 2012

Biosimilars can improve healthcare

• Biosimilars can enable previously restricted therapies to become part of the accepted standard of care

• In the UK, patients have benefited from lower acquisition costs and improvements in the practice of medicine after the approval of a filgrastim biosimilar

• This has enabled the routine use of filgrastim (as a biosimilar) as a first-line treatment for the first time

2007 2008 2009 2010

-2-5

13

17November

2008 biosimilar approved

Note: Zarzio® (filgrastim) is not marketed in the United States.

UK filgrastim volume growth percent change vs. previous year

• Many physicians moved filgrastim back to first-line cancer treatment because of lower biosimilars cost

• G-CSF prevents hospital readmission owing to infection

• Biosimilars are less expensive than originator biologics

• Zarzio “patient support kits” expand patient access:– Patients self-administer at home– Efficiency savings repatriated

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Biosimilars must undergo rigorous testing

• To establish biosimilarity, the sponsor must first show that the candidate is highly similar to the reference originator at the analytical level. This can take multiple iterations in early-stage development before clinical testing may begin

• The sponsor must also perform detailed analysis of the originator reference, especially if the structure and biological function is inadequately defined

Physicochemicalcharacterization

Biologicalcharacterization

Non-clinical

PK/PD

Clinicaltrials

Analytics

Des

ign

spec

ificat

ions

Valid

atio

n

Processdevelopment

Adapted with permission from Macmillan Publishers Ltd: Clin Pharmacol Ther (McCamish M and Woollett G. The state of the art in the development of biosimilars. 91(3):405–417), © 2012

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Examples of copies of biological medicines from largely unregulated markets may not meet today’s rigorous standards

• In the past, copies of biological medicines have been produced in some countries where a rigorous regulatory pathway had not been established for biosimilars

• These are known as copy-biologics, alternative biologics or intended copies of biological products

• They may not meet the current criteria defined by the FDA or EMA for biosimilarity and would not be approved in most regulated markets at the present time without additional testing

• As guidelines are established worldwide to standardize the testing of biosimilars for comparability against an originator product, the development of such products becomes less widespread*

*Barkalow F, Biosimilar monoclonal antibodies. In the pipeline: major players and strategies. Citeline.

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Why immunogenicity testing is essential

• To date, there have been no reports of an approved biosimilar being associated with any unusual or unexpected adverse events, although at least two biosimilars that are currently approved in the EU encountered unwanted antibody development during pre-approval clinical studies

• For a somatropin biosimilar, non-neutralizing antibodies were triggered by increased levels of HCPs

• For an epoetin biosimilar, neutralizing antibodies were triggered leading to premature termination of the clinical trial

• Changes in manufacturing process, however, have been associated with problems with immunogenicity even in novel biological medicines

• Immunogenicity testing is therefore an essential part of the biosimilar testing process

Saenger, P. Current status of biosimilar growth hormone. Int J Pediatr Endocroinol 2009; 370329.Bennett, CL et al. Pure red-cell aplasia and epoetin therapy. NEJM 2004;351:1403–8.Mascaro J, presentation . Mexico, August 15, 2007

Increased incidence of pure red cell aplasia with EPREX® (epoetin) SCRelated to leachables from changes in primary packaging

Immunogenicity of GM-CSFNon-immunogenic in immunosuppressed patients Antibodies in non-immunosuppressed patients

Thrombopoietin immunogenicity Pegylated rHuMGDF: highly immunogenic persistent thrombocytopenia meant development program was stopped

Tryptophan-eosinophilamyalgia syndromeProduction strain changed: purification modified. Unrecognized impurity caused EMS (>1300 cases, 38 deaths)

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Highly regulated markets ensure safe biosimilar medicines

• Biosimilar quality is assured by rigorous testing requirements, which include head-to-head analytical/non-clinical/clinical testing against the reference originator. In addition, the regulatory authorities, such as the European Medicines Agency (EMA) and US FDA, require robustness in manufacturing process

• To date, there have been no reports of a biosimilar medicine in highly regulated markets being associated with any unusual or unexpected adverse events as compared to its originator

• In Europe, no unusual or unexpected clinical events have been observed with biosimilars of somatropin, epoetin, or filgrastim

• In the USA, no unusual or unexpected adverse events have been seen with products approved as follow-on biologics on the basis of abbreviated data packages, including Omnitrope®

McCamish M and Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther 2012;91(3):405–417.

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http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_000408.jsp&mid=WC0b01ac058002958cThe BPCI Act appears in Title VII, subtitle A of the Patient Protection and Affordable Care Act, March 2010.US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012.

Draft revisions to Overarching Guideline; Quality Guideline; Non-clinical and Clinical Guideline

2004 2009 20112006 2007 2008 20122010 20132005

EMEA Legislative Pathway

EMEA Regulatory Guidance [Overarching Guideline] under revision

Product Class Specific Guidelines: Low molecular weight heparin, recombinant Interferon-alpha

Product Class Monoclonal antibodies – non-clinical and clinical issues

Product Class Specific Guideline: Erythropoietin (revised)

Quality Guideline;Non-Clinical and Clinical Guideline (under revision )

Product Class Specific Guidelines: Insulin, G-CSF, Somatropin

Product Class Immunogenicity assessment of monoclonal antibodies

Public Health Service Act amended to allow the approval of biosimilars

Overarching Draft Guidelines on biosimilars

Europe US

Biosimilar regulations in EU and USA: different stages of development

• The EU pioneered the development of biosimilar regulations

• US overarching guidelines issued

Draft revisions to Product Class Specific Guideline: Insulin, low molecular weight heparin

Product Class Follicle stimulating hormone, Interferon-beta

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• USA: a biosimilar is “highly similar to the reference product notwithstanding minor differences in clinically inactive components” and “there are no clinically meaningful differences between the biological product and the reference product in terms of the safety, purity, and potency”

• EU: a similar biological or 'biosimilar' medicine is a biological medicine that is similar to another biological medicine that has already been authorized for use and it does not have any meaningful differences from the reference medicine in terms of quality, safety, or efficacy

The definition of ‘biosimilarity’ in the USA vs EU

McCamish M and Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther 2012;91(3):405–417.Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012. Article 8 of Directive 2001/83, as amended.

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Requirements of clinical studies in the USA and EU• Once a Phase I study establishes that a biosimilar possesses comparable

pharmacokinetic and pharmacodynamic attributes in human subjects to the reference biological medicine, a Phase III study of safety, efficacy, and immunogenicity is usually initiated

• Phase III studies use the most sensitive, homogeneous patient population and clinical endpoint to establish the similarity of the biosimilar to the reference and to be able to detect product-related differences

• If the mechanism of action (MoA) for the reference medicine is known, the biosimilar medicine is expected to have the same MoA for the prescribed conditions based on labeling

• Uses for the biosimilar medicine in its labeling must “have been previously approved for the reference product”

• The extent, duration and timing of studies for evaluation of immunogenicity vary depending on a variety of factors including:>the expected duration of product use, nature of product, known incidence and clinical

consequences of immune response for the reference product, results of analytical comparability studies

Gravel P, Naik A, Le Cotonnec J-Y. Biosimilar rhG-CSFs: how similar are they? Targ Oncol 2012; 7(Suppl 1):S3–S16.US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012.

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Requirements of clinical studies in the USA and EU

• US FDA requires a comparative repeat dose toxicity study in a relevant species (if available) that includes toxicokinetic measurements, systemic exposure, local tolerance, and immunogenicity assessments. EMA suggests a risk-based approach to animal studies, taking into consideration factors such as residual uncertainty at the end of in vitro studies and availability of sensitive species/models for in vivo animal studies

• Both EMA and FDA require a sufficient number of product batches to be tested during physiochemical and functional comparative studies to capture the inherent batch-to-batch variability in product characteristics. The biosimilar is expected to exhibit variability similar to the reference medicine

Chance K. US Biosimilar Guidelines: Summary and Insights 2012. Regulatory Focus April 2012Datamonitor; Pharmaceutical key trends 2011—Biosimilar market overview.

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The biosimilar approval pathways across highly regulated markets are similar

Criteria EU and Australia USA Japan

Biosimilar pathway status

Pathway established Pathway established Pathway established

Clinical trials Mandatory, but extent negotiable

Mandatory, but extent negotiable Phase I studies mandatory, Phase III studies may be abbreviated in some situations

Reference medicine Both biosimilar and originator must have the same MOA. Reference must be marketed in the EU/Australia although EU guidelines indicate that studies utilizing a foreign reference could be acceptable

Both biosimilar and originator must have the same MOA. Reference must be marketed in the USA although US guidelines indicate that studies utilizing a foreign reference could be acceptable

Reference must be approved and marketed in Japan

Formulation Same strength and route of administration, otherwise further studies required

Same strength and route of administration

Same strength and route of administration

Post-marketing safety surveillance

Mandatory along with risk management plan

Tailored to the particular safety and effectiveness concerns associated with the reference medicine, its drug class, clinical use elsewhere, and the biosimilar candidate itself

Plan must be created to trace adverse events and a drug safety report submitted

Datamonitor; Biosimilars global regulatory update, May 2012. Regulatory agency websites.US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012.

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The biosimilar approval pathways across highly regulated markets are similar

Criteria EU USA

Equivalence margins

Not currently defined, but it is expected that equivalence margins will be pre-defined by the sponsor along with a strong scientific justification prior to conduct of clinical trials

Not currently defined, but it is expected that equivalence margins will be pre-defined by the sponsor along with a strong scientific justification prior to conduct of clinical trials

Extrapolation to other indications

Will be permitted providing the mechanism of action is the same as the reference; scientific justifications for extrapolation are required

Scientific justification for extrapolation required, even if the biosimilar and reference have the same mechanism of action: Relevant target receptors for each indication Pattern of molecular signaling upon receptor binding Expression and location of target receptors Relevance of pharmacodynamic measures to mechanism of action Relevance of pharmacokinetic values in different patient populations Differences seen in toxicities for the various conditions of use

in the various patient populations (non-comparative data)

Interchangeability Decision at country level Yes, if assessed by FDA based on adequate clinical data. Substitution decisions made at the state level

US Food and Drug Administration. Guidance for industry. Scientific considerations in demonstrating biosimilarity to a reference product. Draft Guidance. Feb 2012.

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Comparative biosimilar approval pathways across the world

Criteria Canada South Korea India China

Biosimilar pathway status

Pathway established Pathway established

Pathway established (2012) No pathway; copy biological medicines approved as new drugs

Clinical trials Mandatory, but extent negotiable

Phase I studies mandatory, Phase III studies may be abbreviated in some situations

Phase I and Phase III trials mandatory

Mandatory: Phase I–III studies for copy biological medicines with a reference not marketed in China. Phase III studies for copy biological medicines marketed in China

Reference medicine

Reference should be approved and marketed in Canada, unless a waiver is approved

Reference should be approved and marketed in South Korea

Reference should be approved and marketed in India, although some flexibility is allowed if reference is not marketed in India

Not defined

Interchange-ability

Decision at province and territory level

Not defined Not defined Not defined

Formulation Same dosage, form, and route of administration

Dosage, form, and strength must be the same

Same strength and route of administration

Not defined

Post-marketing surveillance

Mandatory along with risk management plan and period safety updates

Pharmacovigilance plan must be submitted

Pharmacovigilance plan must be submitted

Not defined

Datamonitor; Biosimilars global regulatory update, May2012. Regulatory agency websites.Department of Biotechnology. Guidelines on similar biologics: Regulatory requirements for marketing authorization in India, 2012.

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EMA and FDA have rigorous standards for biosimilar applications

Generic/Reference/Biosimilar

Significant biophysical differences

Significant clinical variation from reference

PK Efficacy Tolerability

Interferon-alfa-2a/Roferon-A/Alpheon Yes Yes Yes Yes

Human insulin/Humulin/Insulin Human Rapid Marvel, Insulin Human 30/70 Mix Marvel, and Insulin Human Long Marvel

Insufficient data No Yes No

*Post-approval, the marketing authorization for Filgrastim Ratiopharm was voluntarily withdrawn in 2011 at the request of the marketing authorization holder (Ratiopharm), so 15 biosimilars are currently available. Ahmed I, Kaspar B, and Sharma, U. Biosimilars: Impact of biologic product life cycle and European experience on the regulatory trajectory in the United States. Clin Ther 2012; 34(2):400–419.McCamish M and Woollett G. The state of the art in the development of biosimilars. Clin Pharmacol Ther 2012;91(3):405–417.

• Biosimilar quality is assured by the rigorous testing that is integral to the development and manufacturing process required by regulatory authorities such as the European Medicines Agency and US FDA

• Following 20 marketing applications, the EMA has approved 16 biosimilar medicines*

• Thus far, in the absence of differences in biophysical properties between biosimilars and their originators, no significant clinical variation has been observed

• Examples of EMA-rejected or withdrawn biosimilar applications:

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Country Inception Approval pathway

Argentina Sept 2009Administracion Nacional de Medicamentos, Alimentos y Tecnologia (ANMAT) published biologics and biosimilar approval guidance

Australia June 2006 Agrees to follow CHMP/437/04 Guideline on Similar Biological Medicinal Products

Brazil Dec 2010 Resolution 55/2010 regulates all biologic products

Canada Mar 2010 Guidance for Sponsors: Information and Submission Requirements for Subsequent Entry Biologics

China All biologics, original or copy-biologics undergo the same pathway

Colombia License for Manufacturing Facilities of Biological Products

EU Oct 2005 CHMP/437/04 Guideline on Similar Biological Medicinal Products

EU Nov 2010 Guideline on similar biological medicinal products containing monoclonal antibodies

India Feb 2012201 Department of Biotechnology finalizes guidelines for nonclinical evaluation of similar biologics (biosimilars)

Japan Mar 2009 Guidance issued by Japan’s Ministry of Health, Labour and Welfare

Malaysia July 2008 Guidance Document for Registration of Biosimilars in Malaysia

Mexico June 2009 Article 222 of the General Health Law

Russia Biosimilars are subject to the same regulations as generics

Saudi Arabia Dec 2010 Guidelines on Biosimilars version 1.1

Singapore April 2010 Appendix 17 of the Guidance on Medicinal Product Registration in Singapore

South Korea Sept 2010 Guidelines on the Evaluation of Biosimilar Products

Taiwan Nov 2008Review Criteria for Registration and Market Approval of Pharmaceuticals-Registration and Market Approval of Biological Products

Turkey August 2008 Instruction Manual on Biosimilar Medical Products. Adopted EMA guidance into law 2011

USA March 2010 Law. No. 111–148, The Approval Pathway For Biosimilar Biologic Products

Venezuela August 2000SRPB-R Guidelines: application for Health registry of DNA recombinant products, monoclonal and therapeutic antibodies

Regulatory guidelines for biosimilar approvals are developing at different paces

Datamonitor. Biosimilars global regulatory update, May2012. European Generic Medicines Association, 2010.

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