Biosimilars Clarified

Transcription

1 Biosimilars Clarified 1

2 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 2

3 Biological Products and Biosimilars 3

4 What Are Biological Products? Biological Products Biological products include a wide range of products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins 1 Small Molecules Compared With Biological Products Small Molecule (eg, aspirin) MW=180 Daltons 2 Granulocyte Colony-Stimulating Factor MW=18,800 Daltons 3 Anti-RSV Monoclonal Antibody MW up to 150,000 Daltons 4 MW, molecular weight; RSV, respiratory syncytial virus. Images from shutterstock.com (Image ID, L R: , , ). 1. US FDA. What are biologics questions and answers. cber/ucm htm. Accessed May 3, National Center for Biotechnology Information. 3. Neupogen (filgrastim) injection. Prescribing Information. 4. Synagis (palivizumab). Prescribing Information. 4

5 Biological Products Are Complex, With Distinct Differences Compared With Small Molecules Properties Small Molecules Biological Products Size, Structure, and Composition Small; less complex; uniform 1 Large; highly complex; mixture of related forms 1 Manufacturing Immunogenicity Chemically synthesized 2 Process is easy to replicate/produce 3 Reactions are intrinsic to the patient and not easily attributable to the product 3 Isolated from natural sources and may be produced via biotechnology methods 2 Process is highly elaborate, and variability can exist between batches 4 Reactions may be attributable to both product- and host-related factors 3 1. Siegel J. Rheumatology, ed ; US FDA. What are biologics questions and answers. centersoffices/officeofmedicalproductsandtobacco/cber/ucm htm. Accessed May 3, Genazzani AA, et al. Biodrugs 2007;21: Kuhlmann M, Covic A. Nephrol Dial Transplant 2006;21[suppl 5]:v4 v8. 5

6 Biosimilars: A New Development Originator (Also Known as Reference ) Biological Product Biological product against which a proposed biosimilar is evaluated 1 Biosimilar Highly similar to the originator biologic, notwithstanding minor differences in clinically inactive components 2 No clinically meaningful differences between a biosimilar and an originator in terms of safety, purity, and potency 2 1. US FDA. Overview of the regulatory pathway and FDA s guidance for the development and approval of biosimilar products in the US. UCM pdf. Accessed May 3, US FDA. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product

7 Rationale for Biosimilars A pathway for approving biosimilars was created by the US Biologics Price Competition and Innovation Act of The act created an abbreviated approval pathway for biologics demonstrated to be biosimilar to an originator, as determined by the FDA 2 The goals of the new pathway were to 3 : 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. Accessed May 3, US FDA. Scientific considerations in demonstrating biosimilarity to a reference product US FDA. From our perspective. Biosimilar product labeling. Accessed May 3,

8 Biosimilars Are Not Generics Small-Molecule Generics Generic identical to reference product 1,2 Generics are not required to be evaluated in clinical trials for regulatory approval 2 Biosimilars Manufactured using the same amino acid sequence as the originator biological product 3 Structural and functional differences are rigorously tested in preclinical programs 4 Clinical trials are required to support that there are no clinically meaningful differences 4 1. Siegel J. Rheumatology. Sixth ed. 2015; US FDA. Generic drugs: questions and answers. ResourcesForYou/Consumers/QuestionsAnswers/ucm htm. Accessed May 3, US FDA. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference product US FDA. Scientific considerations in demonstrating biosimilarity to a reference product

9 Biosimilar Development Pathway 9

10 Development Pathways for Originator and Biosimilar Products Are Different 1 Originator Biologic Biosimilar The pathway for originator development is designed to demonstrate that the proposed product is safe and efficacious 1,2 The pathway for biosimilar development is designed to demonstrate biosimilarity between the proposed biological product and the originator product 1,3 1. US FDA. Overview of the regulatory guidance for the development and approval of biosimilar products in the US. pdf. Accessed May 3, US FDA. Providing clinical evidence of effectiveness for human drug and biological products US FDA. Scientific considerations in demonstrating biosimilarity to a reference product

11 Development Pathway: Originator Biological Products vs Biosimilars Originator Biological Products 1-4 Establish safety and efficacy of a new product 4 Biosimilars 5,6 Demonstrate biosimilarity to approved originator biological product using a totality-of-the-evidence approach 5 Sequence of Tests Clinical Trials Animal Testing Analytical Testing Clinical Trials Animal Testing Analytical Testing 1. US FDA. Providing clinical evidence of effectiveness for human drug and biological products Kingham R, et al. Pharmaceutical Sciences Encyclopedia 2013; doi: / pse US FDA. FDA s overview of the regulatory guidance for the development and approval of biosimilar products in the US. DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UC M pdf. Accessed May 3, US FDA. Overview of the regulatory pathway and FDA s guidance for the development and approval of biosimilar products in the US. arthritisadvisorycommittee/ucm pdf. Accessed May 3, US FDA. Scientific considerations in demonstrating biosimilarity to a reference product US FDA. FDA Overview of Biosimilar Products. Accessed May 3,

12 Comprehensive Comparative Analytical Studies Form the Foundation of Biosimilarity Structural Tests Demonstrate that protein structure is highly similar to the originator, with only minor differences in clinically inactive components 1 Comparing: Primary and higher order structure 1 Posttranslational modifications 1 Purity and stability 1 Functional Tests Provide additional data to support structural analyses, investigate consequences of observed structural differences, and explore structure-activity relationships 1 Comparing: Biologic activity 1 Immunochemical properties 2 Potency 1 Demonstrating comprehensive and robust structural and functional similarity allows for selective and targeted animal and/or clinical testing 1 1. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product US FDA. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference protein product

13 Animal Studies May Be Considered to Demonstrate Preclinical Comparability Animal Toxicity Studies 1 Useful when uncertainties remain about safety after extensive structural and functional characterization Comparative studies with the proposed biosimilar and originator biological product Animal PK/PD Measures 1 Single-dose study can be used for evaluation Animal PK/PD studies do not supplant human studies Animal Immunogenicity Studies 1 Comparisons allow identification of potential differences in immunogenicity profiles Inform design of clinical immunogenicity assessments PD, pharmacodynamics; PK, pharmacokinetics. 1. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product

14 Clinical Development Focuses on Demonstrating Biosimilarity to the Originator 1 Robust preclinical data allow for a targeted approach to clinical testing 1 Clinical Pharmacology Studies 1-3 Equivalent PK and PD to originator biological product Comparable safety and immunogenicity Additional Comparative Clinical Studies 1,3 Equivalent efficacy to originator biological product in one indication Comparable safety and immunogenicity in one indication PD, pharmacodynamics; PK, pharmacokinetics. 1. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product US FDA. Clinical pharmacology data to support a demonstration of biosimilarity to a reference product Federal Trade Commission. Emerging health care issues: follow-on biologic drug competition. 2009http:// ucm pdf. Accessed May 3,

15 Immunogenicity Is Rigorously Tested Immunogenicity is assessed extensively because it can arise from any biological product and has the potential to influence efficacy and/or safety 1,2 Image from shutterstock.com (Image ID, ). 1. US FDA. Immunogenicity assessment for therapeutic protein products US FDA. Scientific considerations in demonstrating biosimilarity to a reference product

16 Concept of Extrapolation Extrapolation Granting a biosimilar approval for a range of originator biological product indications based on demonstrated safety and efficacy in one indication 1 After a product has been approved based on Overall comparability with originator biological product using a totality-of-the-evidence approach 2 Safety and efficacy in an appropriate indication 2 MoA, mechanism of action. 1. US FDA. Biosimilars: Questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of US FDA. Scientific considerations in demonstrating biosimilarity to a reference product

17 Clinical Assessment of Biosimilarity 17

18 Clinical Studies to Evaluate Biosimilarity 1 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

19 Study Designs for Originator and Biosimilar Products Comparison of Superiority Design (Originator vs Placebo) and Equivalence Design (Biosimilar vs Originator) 1-3 Originator vs Placebo Biosimilar vs Originator Originator Biosimilar Treatment effect (%) p<0.05 Placebo Treatment effect (%) +Δ Δ Originator Equivalence margin 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 1. US FDA. E9 statistical principles for clinical trials US FDA. Scientific considerations in demonstrating biosimilarity to a reference product Pater C, et al. Curr Control Trials Cardiovasc Med 2004;5:9. 19

20 Considerations for Comparative Clinical Studies for Biosimilars Study Population Should be sensitive to detect differences 1 Can be the same as or different than those used in the originator s clinical studies 1 Sample Size Based on the selected endpoint and margins under the chosen study conditions 1 Duration Endpoints Generally the same as or shorter than the duration of originator trials because not independently establishing safety and efficacy of the product 1 Should reflect activity of the product 1 Can be the same as or different than those used as primary endpoints in the originator s clinical studies 2 1. US FDA. Biosimilar biological products clinical investigator course. ClinicalInvestigatorTrainingCourse/UCM pdf. Accessed May 3, US FDA. Scientific considerations in demonstrating biosimilarity to a reference product

21 Biosimilars Quality Assurance 21

22 Quality Assurance Is Critical for Biological Products Properties of biological products, such as higher order structure and posttranslational modifications, are sensitive to changes in the manufacturing process 1,2 Even minor structural differences can affect the safety and efficacy of a biological product 2 Enhanced approaches to pharmaceutical development, along with quality systems and processes, are integral to the consistent manufacturing of high-quality biosimilars 3 Images from sciencephoto.com (Image ID, left: C017/9435; middle: G255/0130) and shutterstock.com (Image ID, right: ). 1. Mellstedt H, et al. Ann Oncol. 2008;19: US FDA. Scientific considerations in demonstrating biosimilarity to a reference product US FDA. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference protein product

23 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 match 1,2 Biosimilarity is established by the FDA through a stepwise series of analytical, animal, and clinical studies 3 Comparisons of relevant quality attributes are conducted across all manufacturing lots with characterization tests, process controls, and FDA-approved release specifications 2 FDA, US Food and Drug Administration. 1. US FDA. Guidance for industry Q8(R2) pharmaceutical development US FDA. Quality considerations in demonstrating biosimilarity of a therapeutic protein product to a reference protein product US FDA. Scientific considerations in demonstrating biosimilarity to a reference product

24 Merck and Samsung Bioepis: A Unique Partnership to Deliver Biosimilars 1,2 Educating health care professionals and patients Providing support for health care professionals and patients Communicating the value of biosimilars Focusing on our commitment to patient access and well-being (A joint venture of Samsung BioLogics and Biogen) Preclinical and clinical development Process development and 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 1. Merck web site. 125 Year Anniversary. Accessed May 3, Samsung Bioepis. Samsung Bioepis and MSD enter biosimilars development and commercialization agreement. Accessed May 3,

25 Merck: Guiding You Into the Era of Biosimilars Our goal is to improve human health by delivering high-quality, rigorously studied, affordable biosimilars Merck Has Made a Long-Term Commitment to Biosimilars 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 Image from shutterstock.com (Image ID, ). 25

26 Samsung Bioepis: Global Leader in Developing and Manufacturing Quality Biosimilars Samsung Bioepis Brings Its Leadership to Biosimilars 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 US 1 Stringent standards 12% of manufacturing practice used in order to be compliant with regulatory requirements and international industry standards 2 EU, European Union; US, United States. 1. Biogen. Our facilities. Accessed May 3, Samsung BioLogics. Facility overview. Accessed May 3,

27 Pharmacovigilance Programs Continue to Monitor the Long-term Safety of Biosimilars Pharmacovigilance 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 factors 1 Effects of a Robust Pharmacovigilance Program 2 Detection of differences in safety between biosimilar and originator biological product Detection and evaluation of rare but potentially serious emerging safety risks not detected in the smaller clinical trial population In addition to postmarketing studies that are required by the FDA, 2 Merck Samsung Bioepis will perform real-world observational studies to continue monitoring safety FDA, US Food and Drug Administration. 1. US FDA. Good pharmacovigilance practices and pharmacoepidemiologic assessment US FDA. Scientific considerations in demonstrating biosimilarity to a reference product

28 The Potential of Biosimilars 28

29 Rationale for Biosimilars A pathway for approving biosimilars was created by the US Biologics Price Competition and Innovation Act of The act created an abbreviated approval pathway for biologics demonstrated to be biosimilar to an originator as determined by the FDA 2 The goals of the new pathway were to 3 : 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. Accessed May 3, US FDA. Scientific considerations in demonstrating biosimilarity to a reference product US FDA. From our perspective. Biosimilar product labeling. Accessed May 3,

30 Biosimilars Have Been Approved for Use in Several Countries 1-11,a Canada 3 E.U South Korea U.S.A. 2 3 Japan 1 Mexico 63 India 12% 2 Brazil 11 Australia a Only 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. 30

31 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 Europe 1 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 access 1,2 DRUG PRICES PATIENT ACCESS a a In countries with low usage/availability. IMS = Intercontinental Marketing Services. 1. IMS Health. The impact of biosimilar competition IMS Health. The impact of biosimilar competition five observations by IMS Health

32 IMS Health: The Introduction of Biosimilars Drove Down Drug Prices in Europe 1 The three established therapy areas with biosimilar competition show a consistent picture of reduced average prices in European Economic Area countries Biological Product Category PRICE per Treatment Day a (2014/Year before biosimilar entrance) Biosimilar & Originator Total Market Epoetin -28% -27% Granulocyte colonystimulating factor -19% -28% Growth hormone -7% -13% Used with permission from IMS Health a Treatment days (also known as defined daily dose) is a measure of the average dose prescribed as defined by the WHO. 2 IMS = Intercontinental Marketing Services. WHO = World Health Organization. 1. IMS Health. The impact of biosimilar competition five observations by IMS Health IMS Health. The impact of biosimilar competition

33 IMS Health: Introduction of Biosimilars Improved Patient Access in Some Countries 1 Price reductions driven by biosimilar competition contributed to increased patient access in countries where usage/availability was previously low Biological Product Category Country Epoetin Price per Treatment Day a (2014/Year before biosimilar entrance) Volume in Treatment Days a (2014/Year before biosimilar entrance) Romania -42% +457% Bulgaria -51% +166% Granulocyte colonystimulating factor Romania -59% +1621% Poland -44% +474% Growth hormone Slovakia -48% +98% Czech Republic -21% +82% Used with permission from IMS Health a Treatment days (also known as defined daily dose) is a measure of the average dose prescribed as defined by the WHO. 2 IMS = Intercontinental Marketing Services. WHO = World Health Organization. 1. IMS Health. The impact of biosimilar competition five observations by IMS Health IMS Health. The impact of biosimilar competition

34 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 34

35 Summary 35

36 Summary Biosimilars are highly similar to originator biological products, notwithstanding minor differences in clinically inactive components 1 The development pathway for biosimilars focuses on demonstrating biosimilarity to originators using a totality-of-the-evidence approach 1 Clinical trials for biosimilars typically use an equivalence design to establish that the biosimilar is neither inferior nor superior to the originator 1 Merck has partnered with Samsung Bioepis combining our individual strengths to help deliver high-quality biosimilars 2 Biosimilars are being developed to increase treatment options and reduce health care costs 3 1. US FDA. Scientific considerations in demonstrating biosimilarity to a reference product Samsung Bioepis. Samsung Bioepis and MSD enter biosimilars development and commercialization agreement. newsroom_3.html. Accessed May 3, US FDA. From our perspective: biosimilar product labeling. NewsEvents/ucm htm. Accessed May 3,

37 Copyright 2016 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. BIOS /16 37