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Biosimilars Clarified

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Learning Objectives

• Identify the key features of biological products and biosimilars

• Understand the biosimilar development pathway and clinical trials that assess biosimilarity

• Highlight Merck’s commitment to biosimilars

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Biological Products and Biosimilars

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What Are Biological Products?

MW, molecular weight; RSV, respiratory syncytial virus .Images from shutterstock.com (Image ID, L–R: 130253351, 164969582, 102810104).1. US FDA. What are “biologics” questions and answers. http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cber/ucm133077.htm. Accessed May 3, 2016. 2. National Center for Biotechnology Information. 3. Neupogen (filgrastim) injection. Prescribing Information. 4. Synagis (palivizumab). Prescribing Information.

Biological products include a wide range of products such asvaccines, blood and blood components, allergenics, somatic cells,

gene therapy, tissues, and recombinant therapeutic proteins1

Biological Products

Small Molecules Compared With Biological Products

Anti-RSV Monoclonal AntibodyMW up to ≈150,000 Daltons4

Small Molecule (eg, aspirin)

MW=180 Daltons2

Granulocyte Colony-Stimulating Factor

MW=18,800 Daltons3

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Biological Products Are Complex, With Distinct Differences Compared With Small Molecules

Properties Small Molecules Biological Products

Size, Structure, and Composition

Small; less complex; uniform1

Large; highly complex; mixture of related forms1

Manufacturing

Chemically synthesized2

Process is easy to replicate/produce3

Isolated from natural sources and may be produced via biotechnology methods2

Process is highly elaborate, and variability can exist

between batches4

ImmunogenicityReactions are intrinsic

to the patient and not easily attributable to the product3

Reactions may be attributableto both product- andhost-related factors3

1. Siegel J. Rheumatology, ed 6. 2015;522–529. 2. US FDA. What are “biologics” questions and answers. http://www.fda.gov/aboutfda/centersoffices/officeofmedicalproductsandtobacco/cber/ucm133077.htm. Accessed May 3, 2016.3. Genazzani AA, et al. Biodrugs 2007;21:351–356. 4. Kuhlmann M, Covic A. Nephrol Dial Transplant 2006;21[suppl 5]:v4–v8.

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Biosimilars: A New Development

Biological product against which a proposed biosimilar is evaluated1

• Highly similar to the originator biologic, notwithstanding minor differences in clinically inactive components2

• No clinically meaningful differences between a biosimilar and an originator in terms of safety, purity, and potency2

Originator (Also Known as “Reference”) Biological Product

Biosimilar

1. US FDA. Overview of the regulatory pathway and FDA’s guidance for the development and approval of biosimilar products in the US. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM431118.pdf. Accessed May 3, 2016. 2. US FDA. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. 2015.

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Rationale for Biosimilars

• A pathway for approving biosimilars was created by the US Biologics Price Competition and Innovation Act of 20091

• The act created an abbreviated approval pathway for biologics demonstrated to be biosimilar to an originator, as determined by the FDA2

• The goals of the new pathway were to3:

– Increase treatment options

– Reduce health care costs

FDA, US Food and Drug Administration.1. Title VII—Improving Access to Innovative Medical Therapies. Subtitle A—Biologics Price Competition and Innovation. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ucm216146.pdf. Accessed May 3, 2016. 2. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015. 3. US FDA. From our perspective. Biosimilar product labeling. http://www.fda.gov/Drugs/NewsEvents/ucm493240.htm. Accessed May 3, 2016.

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Biosimilars Are Not Generics

• Generic identical to reference product1,2

• Generics are not required to be evaluated in clinical trials for regulatory approval2

• Manufactured using the same amino acid sequence as the originator biological product3

• Structural and functional differences are rigorously tested in preclinical programs4

• Clinical trials are required to support that there are no clinically meaningful differences4

Small-Molecule Generics Biosimilars

1. Siegel J. Rheumatology. Sixth ed. 2015;522–529. 2. US FDA. Generic drugs: questions and answers. http://www.fda.gov/Drugs/ResourcesForYou/Consumers/QuestionsAnswers/ucm100100.htm. Accessed May 3, 2016. 3. US FDA. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product. 2015.4. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015.

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Biosimilar Development Pathway

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Development Pathways for Originator and Biosimilar Products Are Different1

Originator Biologic

1. US FDA. Overview of the regulatory guidance for the development and approval of biosimilar products in the US. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/OncologicDrugsAdvisoryCommittee/UCM431118.pdf. Accessed May 3, 2016. 2. US FDA. Providing clinical evidence of effectiveness for human drug and biological products. 1998. 3. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015.

The pathway for biosimilar development is designed to demonstrate biosimilarity between the proposed biological product and the originator product1,3

Biosimilar

The pathway for originator development is designed to demonstrate that the proposed product is safe and efficacious1,2

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Originator Biological Products1-4

Establish safety and efficacy of a new product4

Development Pathway: Originator Biological Products vs Biosimilars

1. US FDA. Providing clinical evidence of effectiveness for human drug and biological products. 1998. 2. Kingham R, et al. Pharmaceutical Sciences Encyclopedia 2013; doi:10.1002/9780470571224.pse503. 3. US FDA. FDA’s overview of the regulatory guidance for the development and approval of biosimilar products in the US. http://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM428732.pdf. Accessed May 3, 2016. 4. US FDA. Overview of the regulatory pathway and FDA’s guidance for the development and approval of biosimilar products in the US. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/arthritisadvisorycommittee/ucm486171.pdf. Accessed May 3, 2016. 5. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015. 6. US FDA. FDA Overview of Biosimilar Products. http://fdabiosimilars.e-paga.com/course/framework/. Accessed May 3,2016.

Biosimilars5,6

Demonstrate biosimilarity to approved originator biological product using a “totality-of-the-evidence” approach5

Clinical Trials

Animal Testing

AnalyticalTesting

Analytical Testing

Animal Testing

ClinicalTrials

Sequ

ence

of T

ests

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Demonstrating comprehensive and robust structural and functional similarity allows for selective and targeted animal and/or clinical testing1

Comprehensive Comparative Analytical Studies Form the Foundation of Biosimilarity

Demonstrate that protein structure is highly similar to the originator, with only minor differences in clinically inactive components1

Provide additional data to support structural analyses, investigate consequences of observed structural differences, and explore structure-activity relationships1

Comparing:• Primary and higher

order structure1

• Posttranslational modifications1

• Purity and stability1

1. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015. 2. US FDA. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference protein product. 2015.

Comparing:• Biologic activity1

• Immunochemical properties2

• Potency1

Structural Tests Functional Tests

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• Single-dose study can be used for evaluation• Animal PK/PD studies do not supplant human

studies

• Comparisons allow identification of potential differences in immunogenicity profiles

• Inform design of clinical immunogenicity assessments

• Useful when uncertainties remain about safety after extensive structural and functional characterization

• Comparative studies with the proposed biosimilar and originator biological product

Animal Studies May Be Considered to Demonstrate Preclinical Comparability

PD, pharmacodynamics; PK, pharmacokinetics.1. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015.

Animal Toxicity Studies1

Animal PK/PD Measures1

Animal Immunogenicity

Studies1

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Clinical Development Focuses on Demonstrating Biosimilarity to the Originator1

PD, pharmacodynamics; PK, pharmacokinetics.1. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015. 2. US FDA. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. 2014. 3. Federal Trade Commission. Emerging health care issues: follow-on biologic drug competition. 2009http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/arthritisadvisorycommittee/ucm486171.pdf. Accessed May 3, 2016.

Robust preclinical data allow for a targeted approach to clinical testing1

• Equivalent PK and PD to originator biological product

• Comparable safety and immunogenicity

• Equivalent efficacy to originator biological product in one indication

• Comparable safety and immunogenicity in one indication

Clinical Pharmacology Studies1-3

Additional Comparative Clinical Studies1,3

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Immunogenicity Is Rigorously Tested

Image from shutterstock.com (Image ID, 252647446).1. US FDA. Immunogenicity assessment for therapeutic protein products. 2014. 2. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015.

Immunogenicity is assessed extensively because it can arise from any biological product and has the potential to influence efficacy and/or safety1,2

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After a product has been approved based on…• Overall comparability with originator biological product using a

“totality-of-the-evidence” approach2

• Safety and efficacy in an appropriate indication2

Concept of Extrapolation

MoA, mechanism of action.1. US FDA. Biosimilars: Questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009. 2015. 2. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015.

Granting a biosimilar approval for a range of originator biological product indications based on demonstrated safety and efficacy in one indication1

Extrapolation

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Clinical Assessment of Biosimilarity

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Clinical Studies to Evaluate Biosimilarity1

• Biosimilars are expected to have no clinically meaningful differences compared with the originator biological product

• To investigate whether there are clinically meaningful differences between a proposed biosimilar and the originator product, comparative clinical studies are required

• An equivalence design establishes that the biosimilar is neither inferior nor superior to the originator

1. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015.

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Study Designs for Originator and Biosimilar Products

1. US FDA. E9 statistical principles for clinical trials. 1998. 2. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015. 3. Pater C, et al. Curr Control Trials Cardiovasc Med 2004;5:9.

Comparison of Superiority Design (Originator vs Placebo) and Equivalence Design (Biosimilar vs Originator)1-3

Trea

tmen

t effe

ct (%

)

Originator vs Placebo

OriginatorPlacebo

p<0.05

Trea

tmen

t effe

ct (%

)

BiosimilarOriginator

Biosimilar vs Originator

Equivalence margin

–Δ

+Δ

Graphs are for illustrative purposes.

Equivalence studies require that the predefined confidence interval of treatment difference falls within the equivalence margin (between –Δ and +Δ)2,3

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Considerations for Comparative Clinical Studies for Biosimilars

• Should reflect activity of the product1• Can be the same as or different than those used as

primary endpoints in the originator’s clinical studies2Endpoints

• Should be sensitive to detect differences1

• Can be the same as or different than those used in the originator’s clinical studies1

Study Population

• Based on the selected endpoint and margins under the chosen study conditions1Sample Size

• Generally the same as or shorter than the duration of originator trials because not independently establishing safety and efficacy of the product1

Duration

1. US FDA. Biosimilar biological products - 2013 clinical investigator course. http://www.fda.gov/downloads/Training/ClinicalInvestigatorTrainingCourse/UCM378510.pdf. Accessed May 3, 2016. 2. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015.

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Biosimilars Quality Assurance

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Quality Assurance Is Critical for Biological Products

• Properties of biologicalproducts, such as higher order structure and posttranslational modifications, are sensitive to changes in the manufacturing process1,2

• Even minor structural differences can affect the safety and efficacy of a biological product2

Images from sciencephoto.com (Image ID, left: C017/9435; middle: G255/0130) and shutterstock.com (Image ID, right: 77425762).1. Mellstedt H, et al. Ann Oncol. 2008;19:411–419. 2. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015. 3. US FDA. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference protein product. 2015.

Enhanced approaches to pharmaceutical development, along with quality systems and processes, are integral to the

consistent manufacturing of high-quality biosimilars3

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Quality of Biosimilars Is Built in by Design

A target product profile is identified, including key physiologic, biologic, and clinical attributes of the originator that the biosimilar must match1,2

Biosimilarity is established by the FDA through a stepwise series of analytical, animal, and clinical studies3

Comparisons of relevant quality attributes are conducted across all manufacturing lots with characterization tests, process controls, and FDA-approved release specifications2

FDA, US Food and Drug Administration.1. US FDA. Guidance for industry Q8(R2) pharmaceutical development. 2009.2 US FDA. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference protein product. 2015. 3. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015.

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Merck and Samsung Bioepis: A Unique Partnership to Deliver Biosimilars1,2

1. Merck web site. 125 Year Anniversary. http://www.merck.com/about/featured-stories/125th_anniversary.html. Accessed May 3, 2016. 2. Samsung Bioepis. Samsung Bioepis and MSD enter biosimilars development and commercialization agreement. http://www.samsungbioepis.com/newsroom2/newsroom_3.html. Accessed May 3, 2016.

Educating health care professionals and patients

Providing support for health care professionals and patients

Communicating the valueof biosimilars

Focusing on our commitment to patient access and

well-being

(A joint venture of Samsung BioLogics and Biogen)

Preclinical andclinical development

Process developmentand manufacturing

Clinical trials

Regulatory approval/ registration

125 years of pharmaceutical experience plus commitment to

biosimilars

Expertise in large-scale biological product development

and technical innovation

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Merck: Guiding You Into the Era of Biosimilars

Image from shutterstock.com (Image ID, 144194431).

• We are bringing a full portfolio of biosimilars to market across multiple therapeutic areas

• We have the experience and capabilities to bring these new options to patients

Merck Has Made a Long-Term Commitment to Biosimilars

Our goal is to improve human health by delivering high-quality, rigorously studied, affordable biosimilars

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12%

Samsung Bioepis: Global Leader in Developing and Manufacturing Quality Biosimilars

EU, European Union; US, United States.1. Biogen. Our facilities. https://www.biogen.com/en_us/about-biogen/our-facilities.html. Accessed May 3, 2016. 2. Samsung BioLogics. Facility overview. https://www.samsungbiologics.com/manufac/facility.do. Accessed May 3, 2016.

• Samsung Bioepis is a joint venture between Samsung BioLogics and Biogen

• Expertise in large-scale biological product development and technical innovation

• State-of-the-art manufacturing facilities in EU and US1

• Stringent standards of manufacturing practice used in order to be compliant with regulatory requirements and international industry standards2

Samsung Bioepis Brings Its Leadership to Biosimilars

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Pharmacovigilance Programs Continue to Monitor the Long-term Safety of Biosimilars

FDA, US Food and Drug Administration.1. US FDA. Good pharmacovigilance practices and pharmacoepidemiologic assessment. 2005. 2. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015.

In addition to postmarketing studies that are required by the FDA,2Merck–Samsung Bioepis will perform real-world observational

studies to continue monitoring safety

• Detection of differences in safety between biosimilar and originatorbiological product

• Detection and evaluation of rare but potentially serious emerging safety risks not detected in the smaller clinical trial population

Effects of a Robust Pharmacovigilance Program2

Definition: Scientific and data-gathering activities relating to detection, assessment, and understanding of adverse events, with the goal of identifying adverse events to better understand their nature, frequency, and potential risk factors1Pharmacovigilance

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The Potential of Biosimilars

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Rationale for Biosimilars

• A pathway for approving biosimilars was created by the US Biologics Price Competition and Innovation Act of 20091

• The act created an abbreviated approval pathway for biologics demonstrated to be biosimilar to an originator as determined by the FDA2

• The goals of the new pathway were to3:

– Increase treatment options

– Reduce health care costs

FDA, US Food and Drug Administration.1. Title VII—Improving Access to Innovative Medical Therapies. Subtitle A—Biologics Price Competition and Innovation. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/ucm216146.pdf. Accessed May 3, 2016. 2. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015. 3. US FDA. From our perspective. Biosimilar product labeling. http://www.fda.gov/Drugs/NewsEvents/ucm493240.htm. Accessed May 3, 2016.

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Biosimilars Have Been Approved for Use in Several Countries1-11,a

aOnly select countries with approved biosimilars are highlighted; number of approved biosimilars in each country/region updated Apr 2016 (India and Japan), Mar 2016 (U.S.), Feb 2016 (E.U. and Australia), Jan 2016 (Mexico, Brazil, and South Korea), and Dec 2014 (Canada). 1. Generics and Biosimilars Initiative. Subsequent entry biologics approved in Canada. 2. Generics and Biosimilars Initiative. Biosimilars approved in the US. 3. Generics and Biosimilars Initiative. Similar biotherapeutic products approved and marketed in Latin America. 4. Generics and Biosimilars Initiative. Biosimilars approved in Europe. 5. Generics and Biosimilars Initiative. Trastuzumab non-originator biological approved in Russia. 6. Generics and Biosimilars Initiative. Iran approves its first rituximab biogeneric. 7. Generics and Biosimilars Initiative. Similar biologics’ approved and marketed in India. 8. Generics and Biosimilars Initiative. Biosimilars approved in South Korea. 9. Generics and Biosimilars Initiative. Biosimilars approved in Japan. 10. Generics and Biosimilars Initiative. Biosimilars approved in Australia. 11. Generics and Biosimilars Initiative. Biosimilars approved in New Zealand.

12%

2U.S.A.

Canada3 E.U. 22

Australia11

3 Japan

India63

3 SouthKorea

Brazil2

1

Mexico

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Biosimilars Have Impacted Drug Prices and Patient Access in the European Market

• At the request of the European Commission, IMS Health investigated the impact of biosimilar competition on drug price, volume, and market share in Europe1

• The first annual report, which evaluated 2014 data, suggests biosimilar competition was responsible for lower drug prices, and, in countries with low drug usage/availability, greater patient access1,2

aIn countries with low usage/availability.IMS = Intercontinental Marketing Services.1. IMS Health. The impact of biosimilar competition. 2015. 2. IMS Health. The impact of biosimilar competition – five observations by IMS Health. 2015.

DRUGPRICES

PATIENTACCESSa

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IMS Health: The Introduction of Biosimilars Drove Down Drug Prices in Europe1

“The three established therapy areas with biosimilar competition show a consistent picture of reduced average prices in European Economic Area countries”

Used with permission from IMS Health. 2015.1aTreatment days (also known as defined daily dose) is a measure of the average dose prescribed as defined by the WHO.2IMS = Intercontinental Marketing Services. WHO = World Health Organization. 1. IMS Health. The impact of biosimilar competition – five observations by IMS Health. 2015. 2. IMS Health. The impact of biosimilar competition. 2015.

PRICE per Treatment Daya

(2014/Year before biosimilar entrance)Biological Product Category

Biosimilar & Originator

Total Market

Epoetin -28% -27%Granulocyte colony-stimulating factor -19% -28%

Growth hormone -7% -13%

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IMS Health: Introduction of Biosimilars Improved Patient Access in Some Countries1

Price reductions driven by biosimilar competition contributed to increased patient access in countries where usage/availability was previously low

Used with permission from IMS Health. 2015.1aTreatment days (also known as defined daily dose) is a measure of the average dose prescribed as defined by the WHO.2IMS = Intercontinental Marketing Services. WHO= World Health Organization. 1. IMS Health. The impact of biosimilar competition – five observations by IMS Health. 2015. 2. IMS Health. The impact of biosimilar competition. 2015.

Biological ProductCategory

Country

Price per Treatment Daya

(2014/Year before biosimilar entrance)

Volume in Treatment Daysa

(2014/Year before biosimilar entrance)

EpoetinRomania -42% +457%

Bulgaria -51% +166%

Granulocyte colony-stimulating factor

Romania -59% +1621%

Poland -44% +474%

Growth hormoneSlovakia -48% +98%

Czech Republic -21% +82%

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Translating EU Experience to the US Market

• How the introduction of biosimilars will affect pricing and patient access in the US remains to be seen

• History of introduction and use in the EU market may or may not translate to the US market, given the marked differences in health care systems

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Summary

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Summary

• Biosimilars are highly similar to originator biological products, notwithstanding minor differences in clinically inactive components1

• The development pathway for biosimilars focuses on demonstrating biosimilarity to originators using a “totality-of-the-evidence” approach1

• Clinical trials for biosimilars typically use an equivalence design to establish that the biosimilar is neither inferior nor superior to the originator1

• Merck has partnered with Samsung Bioepis – combining our individual strengths – to help deliver high-quality biosimilars2

• Biosimilars are being developed to increase treatment options and reduce health care costs3

1. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product. 2015. 2. Samsung Bioepis. Samsung Bioepisand MSD enter biosimilars development and commercialization agreement. http://www.samsungbioepis.com/newsroom2/newsroom_3.html. Accessed May 3, 2016.3. US FDA. From our perspective: biosimilar product labeling. http://www.fda.gov/Drugs/NewsEvents/ucm493240.htm. Accessed May 3, 2016.

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