Understanding the Expanding Role of Biosimilars in Quality Cancer Care Supported by independent medical education grants from Pfizer Inc. and Sandoz Inc., a Novartis Division.

Biosimilars in Oncology: Insights Into the Development and Evaluation Process Rowena Schwartz, PharmD, BCOP Associate Professor University of Cincinnati Cincinnati, Ohio

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Faculty Program Director: Gary Lyman, MD, MPH, FASCO Co-Director, Hutchinson Institute for Cancer Outcomes Research (HICOR) Public Health Sciences and Clinical Research Divisions Fred Hutchinson Cancer Research Center Professor of Medicine/Medical Oncology University of Washington School of Medicine Seattle, Washington Jeffrey Crawford, MD George Barth Geller Professor of Medicine Duke University Co-Director Solid Tumor Therapeutics Program Duke Cancer Institute Durham, North Carolina Rowena Schwartz, PharmD, BCOP Associate Professor University of Cincinnati Cincinnati, Ohio This slide lists the faculty who were involved in the production of these slides.

Faculty Disclosures Gary Lyman, MD, MPH, FASCO, has disclosed that he has received funds for research support (principal investigator) paid to his institution from Amgen. Jeffrey Crawford, MD, has disclosed that he has received consulting fees from Merck, Novartis, and Pfizer; fees for non-CME services from Beyond Spring, Celgene, G1 Therapeutics, Janssen, Merrimack, and Roche; and funds for research support (principal investigator) paid to his institution from Amgen, AstraZeneca, and Bayer. Rowena Schwartz, PharmD, BCOP, has disclosed that she has received salary from McKesson (employment ended August 2016) and owns stock in McKesson. This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

“Hand clapping for science is now inextricably linked to hand wringing over affordability.” Bach PB. N Engl J Med. 2015;373:1797-1799.

The Beginning of the Conversation About Biosimilars . . . 2013 1982 First biopharmaceutical: recombinant human insulin[1] End of US patent exclusivity for filgrastim[2] 1. FDA. Celebrating a milestone: FDA's approval of first genetically-engineered product. 2007. 2. Lucio SD, et al. Am J Health Syst Pharm. 2013;70:2004-2017. Slide credit: clinicaloptions.com

Definition of a Biologic US Federal Code of Regulation defines biologic as “any virus, therapeutic serum, toxin, antitoxin, or analogous product applicable to the prevention, treatment, or cure of disease or injuries”[1] First developed in the 1980s using recombinant DNA technology[2] Includes a wide range of products[2] Slide credit: clinicaloptions.com 1. FDA. CFR title 21, vol 7. Updated 2016. 2. McCamish M, et al. Clin Pharmacol Ther. 2012;9:24.

What Are Biosimilars? Biosimilars: biological product highly similar to reference product with minor differences in clinically inactive components No clinically meaningful differences between biosimilar product and reference product in terms of safety, efficacy, purity, and potency FDA approval process outlined in Affordable Care Act[1] Simplification of development process designed to reduce production costs and encourage competition[2] 1. FDA. Information on biosimilars. 2016. 2. Cornes P. Target Oncol. 2012;7:57-67. Slide credit: clinicaloptions.com

Complexity of Biologics Each manufacturer uses a proprietary process and unique cell line for production of a particular biologic agent Even slight changes in the manufacturing process can result in a different end product Inability to produce an exact copy of a biologic, thus the term biosimilar vs biogeneric or bioidentical Slide credit: clinicaloptions.com Ventola CL. P T. 2013;38:270-287.

What Biosimilars Are Not Biosimilars are different than: Generics Second-generation biologics Next-generation biologics Biobetters Intended copies Slide credit: clinicaloptions.com Olech E. Semin Arthritis Rheum. 2016;45(5 suppl):S1-S10.

Biologics vs Small-Molecule Drugs Characteristics Conventional Drugs Biologics Size[1] Small (100-1000 Da) Large (18,000-145,000 Da) Product[1] Chemical based Protein based Structure[2] Simple Complex Stability[2] Stable Unstable Manufacturing[2] Defined, reproducible chemical process Identical copies can be made Unique biological processes within living cell lines Impossible to ensure identical copies Characterization[2] Easy to fully characterize Difficult to fully characterize; heterogeneous mixture of related molecules Immunogenicity[2] Mostly nonimmunogenic Immunogenic Slide credit: clinicaloptions.com 1. Schellekens H. NDT Plus. 2009;2:i27-i36. 2. Mayden KD, et al. J Adv Pract Oncol. 2015;6:108-116.

Nomenclature Example: Filgrastim-sndz and Tbo-filgrastim Biosimilar is a regulatory term Filgrastim-sndz: first FDA-approved biosimilar (2015) Biologics licensed as innovator molecules in the US are not called biosimilars Tbo-filgrastim is licensed in the US as an innovator molecule, not a biosimilar However, Tbo-filgrastim is licensed as a biosimilar in other countries (and in the literature) Slide credit: clinicaloptions.com

US Regulatory and Approval Pathway for Nonbiologics Nonbiologic Drug Approval New Drug (NDA) Must demonstrate safety and efficacy Generic (Abbreviated NDA) Must demonstrate bioequivalence to marketed agent Non-biologic drugs are approved under the Federal Food, Drug, and Cosmetic Act (FDCA) Slide credit: clinicaloptions.com FDA. Federal Food, Drug, and Cosmetic Act (FD&C Act). Updated 2017.

US Regulatory and Approval Pathway for Biologics Biologic Drug Approval Biologics License Application (BLA) Must demonstrate safety and efficacy Biosimilar BLA (abbreviated process) Must demonstrate “highly similar” to marketed agent Interchangeable: additional data required Biologic drugs approved under Public Health Service Act[1] Biosimilars approved under Biologic Price Competition and Innovation Act[2] 1. FDA. Guidance for industry reference product exclusivity for biological products filed under section 351(a) of the PHS Act. 2014. 2. FDA. Implementation of the Biologics Price Competition and Innovation Act of 2009. Updated 2016. Slide credit: clinicaloptions.com

Biologic Price Competition and Innovation Act of 2009 A biological product is biosimilar to a reference product based on data looking at safety, purity, and potency Based on preclinical and clinical studies of pharmacology, efficacy, safety, and immunogenicity Subject to postmarketing surveillance There are different standards for biosimilarity and interchangeability Approval requirements can vary by product Slide credit: clinicaloptions.com FDA. Summary of Biologics Price Competition and Innovation Act of 2009. Updated 2010.

Demonstrating Similarity for Biologics According to the Biologic Price Competition and Innovation Act of 2009, a biological product is biosimilar to a reference product based on: Analytical studies demonstrating a high degree of similarity Animal studies including toxicity assessment Clinical study(ies) demonstrating safety, purity, and potency Demonstration that the products utilize the same mechanism(s) of action for condition(s) of use Demonstration that route of administration, dosage form, and strength are the same as for reference product FDA uses a “totality of the evidence” approach Slide credit: clinicaloptions.com FDA. Biologics Price Competition and Innovation Act of 2009.

US Regulatory and Approval Pathway for Biosimilars Analytical studies structure and function At each step, FDA evaluates totality of evidence to determine if further studies are required to eliminate residual uncertainty between biosimilar and reference biologic Animal studies PK/PD, immunogenicity, toxicity Clinical studies PK/PD, immunogenicity, toxicity PD, pharmacodynamics; PK, pharmacokinetics. (If uncertainty remains) Comparative clinical studies to determine equivalence (dose ranging, efficacy, safety) FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. 2015. Olech E. Semin Arthritis Rheum. 2016;45(5 suppl):S1-S10. Slide credit: clinicaloptions.com

Demonstrating Similarity for Biologics: Analysis Analytical studies: Structure Amino acid sequence, higher-order structures, glycosylation, pegylation Analyze lot-to-lot variability Function Evaluate pharmacologic activity via in vitro or in vivo experiments Functional evaluation that compares candidate to reference product Slide credit: clinicaloptions.com https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf.

Demonstrating Similarity for Biologics: Comparative Clinical Trials Requirements FDA Position Comparative PK studies Human studies are required Comparative PD studies Human studies recommended where clinical relevant markers available, but PK/PD maybe assessed in parallel Comparative clinical equivalence trials A minimum of 1 adequately powered equivalence trial in a population that allows for an assessment of clinically meaningful differences between the originator and biosimilar Safety A minimum of 1 adequately powered equivalence trial to demonstrate highly similar safety profiles Immunogenicity Required PD, pharmacodynamics; PK, pharmacokinetics. FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry. 2015. Slide credit: clinicaloptions.com

Demonstrating Similarity for Biologics: Immunogenicity Human immune responses to a biosimilar may affect safety and effectiveness of the product At least 1 clinical study including a comparison of immunogenicity between the biosimilar and reference product is required FDA recommends use of a comparative parallel design (ie, a head- to-head study) in treatment-naive pts, typically with 1 yr of follow-up Postmarketing surveillance may be warranted FDA. Considerations in demonstrating biosimilarity to a reference product: guidance for industry. 2015. Slide credit: clinicaloptions.com

Biosimilars: Indication Extrapolation Approval of a biosimilar is often based on clinical trials conducted in only one approved indication of the reference product With sufficient clinical data, applicant may seek approval for extrapolation to additional indications for which the reference product is licensed[1] Slide credit: clinicaloptions.com FDA. Considerations in Demonstrating Biosimilarity to a Reference Product: Guidance for Industry. 2015

Biosimilars: Interchangeability Interchangeability implies the ability to switch from reference biologic to biosimilar without authorization from the prescribing health care provider[1] FDA requires additional criteria for interchangeability designation, including demonstration of no loss of safety or efficacy when biosimilar switched or alternated with, not just compared with, US licensed reference biologic[2] Interchangeability is a higher bar than biosimilarity [3] 1. Ventola CL, P T. 2013;38:329-335; 2. FDA. Considerations in Demonstrating Interchangeability With a Reference Product: Guidance for Industry. 2017. 3. Ebbers HS, et al. GaBI J. 2014;3:88-93. Slide credit: clinicaloptions.com

Biosimilars: FDA Naming Convention Etanercept-szzs Core name FDA-designated suffix No recognizable meaning 4 letters Lowercase Filgrastim-sndz Infliximab-abda Adalimumab-atto Infliximab-dyyb Naming may be important for pharmacovigilance of specific products once marketed[1] Slide credit: clinicaloptions.com FDA. Nonproprietary naming of biological products: guidance for industry. 2017.

Biosimilars: Issues in Practical Use Formulary analysis Therapeutic substitution Pharmacovigilance Economics of biosimilars Provider and pt education Slide credit: clinicaloptions.com Lucio SD, et al. Am J Health Syst Pharm. 2013;70:2004-2017.

Conclusions Biosimilar does not equal generic Approval pathway is often simpler than reference biologic but more complex than generic and includes: Analytic studies of structure, function Comparative studies of PK, PD, clinical trials Studies of safety and immunogenicity Biosimilars can apply for: Extrapolation to additional indications of the reference product (granted to ALL US biosimilars to date) Interchangeability status (granted to NO US biosimilars to date) PD, pharmacodynamics; PK, pharmacokinetics.

Go Online for More Coverage of Biosimilars and ASCO 2017! On-Demand Webcast: Understanding the Expanding Role of Biosimilars in Quality Cancer Care (Available at: education.nccn.org/biosimilars) Downloadable summary slidesets of key ASCO 2017 presentations on GU and hematologic malignancies and skin, lung, GI, and breast cancers CME-certified Expert Analysis on key studies presented at ASCO 2017 clinicaloptions.com/oncology