1. 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.

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

3. About These Slides
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Slide credit: clinicaloptions.com
Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

4. 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.

5. 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.

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

7. 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 Lucio SD, et al. Am J Health Syst Pharm. 2013;70:
Slide credit: clinicaloptions.com

8. 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 McCamish M, et al. Clin Pharmacol Ther. 2012;9:24.

9. 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 Cornes P. Target Oncol. 2012;7:57-67.
Slide credit: clinicaloptions.com

10. 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:

11. 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.

12. Biologics vs Small-Molecule Drugs
Characteristics
Conventional Drugs
Biologics
Size[1]
Small ( Da)
Large (18, ,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-i Mayden KD, et al. J Adv Pract Oncol. 2015;6:

13. 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

14. 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.

15. 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 FDA. Implementation of the Biologics Price Competition and Innovation Act of Updated 2016.
Slide credit: clinicaloptions.com

16. 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 Updated 2010.

17. 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.

18. 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 Olech E. Semin Arthritis Rheum. 2016;45(5 suppl):S1-S10.
Slide credit: clinicaloptions.com

19. 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

20. 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
Slide credit: clinicaloptions.com

21. 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
Slide credit: clinicaloptions.com

22. 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

23. 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: ; 2. FDA. Considerations in Demonstrating Interchangeability With a Reference Product: Guidance for Industry Ebbers HS, et al. GaBI J. 2014;3:88-93.
Slide credit: clinicaloptions.com

24. 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

25. 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:

26. 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.

27. 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