1. Expert Answers to Frequently Asked Questions About Biosimilars
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3. Faculty
Sanjiv S. Agarwala, MD Professor of Medicine, Temple University Chief, Medical Oncology & Hematology
St Luke’s Cancer Center
Bethlehem, Pennsylvania
Alan J. Kivitz, MD, CPI President Altoona Arthritis and Osteoporosis Center Altoona Center for Clinical Research Duncansville, Pennsylvania
This slide lists the faculty who were involved in the production of these slides.

4. Faculty
Robert M. Rifkin, MD, FACP Clinical Associate Professor of Medicine Division of Medical Oncology Department of Internal Medicine University of Colorado, Denver Aurora, Colorado  Medical Director, Biosimilars McKesson Specialty Health The US Oncology Network The Woodlands, Texas
Kenneth G. Saag, MD, MSc Jane Knight Lowe Professor Division of Clinical Immunology and Rheumatology Vice Chair, Department of Medicine
Director, Center for Education and Research on Therapeutics Center for Outcomes, Effectiveness Research and Education Center of Research Translation in Gout and Hyperuricemia
University of Alabama at Birmingham
Birmingham, Alabama
This slide lists the faculty who were involved in the production of these slides.

5. Faculty Disclosures
Sanjiv S. Agarwala, MD, has no real or apparent conflicts of interest to report. Alan J. Kivitz, MD, CPI, has disclosed that he has received consulting fees from AbbVie, Celgene, Genentech, Janssen, Merck, Novartis, Pfizer, Regeneron, Sanofi Genzyme, and UCB. Robert M. Rifkin, MD, FACP, has disclosed that he receives a salary from McKesson Specialty Health and has served on advisory boards for Amgen, Coherus, EMD Serono, and Pfizer. Kenneth G. Saag, MD, MSc, has disclosed that he has received consulting fees from Abbott, Amgen, Ardea Biosciences/AstraZeneca, Bayer, Bristol- Myers Squibb, Merck, and Roche/Genentech.
This slide lists the disclosure information of the faculty and staff involved in the development of these slides.

6. What Are Biosimilars?
Biologic products designed to mimic existing, approved biologic agents
Not identical to reference biologic
FDA approval process outlined in Affordable Care Act[1]
Biosimilars must demonstrate no clinically meaningful differences in safety and efficacy from reference biologic
Minor variations in clinically inactive components permitted
Simplification of development process anticipated to reduce production costs and encourage competition[2]
Slide credit: clinicaloptions.com
1. FDA. Information on biosimilars Cornes P. Target Oncol. 2012;7:57-67.

7. How Do Biosimilars vs Small Molecule Generics Compare?
Characteristic
Biosimilar
Generic
Structure
Large, complex biologic molecule
Small, simple, reproducible molecule
Comparison to reference agent
Same amino acid sequence
May differ in posttranslational modifications, protein folding, impurities, excipients[1]
Higher potential for immunogenicity[1]
Identical active ingredients
Same dosage, route of administration, indications, bioequivalence, strength, purity, quality[2]
Manufacturing process[3]
Created in living systems
Unique cell lines and set of production steps
Chemical synthesis
Predictable set of chemical reactions
FDA approval process
Biosimilar Biologics License Application[4]
Demonstrate similar safety, purity, potency, and efficacy[5]
Abbreviated New Drug Application[5]
Demonstrate bioequivalence[1]
1. Li E, et al. J Manag Care Spec Pharm. 2015;21: FDA. What are generic drugs? Jeske W, et al. Drug Healthc Patient Saf. 2013;5: FDA. Information for industry (biosimilars) FDA. Information on biosimilars
Slide credit: clinicaloptions.com

8. What Features Do Biosimilars Share With Their Reference Biologics?
Host cell line
Host cell line
Manufacturing
processes
Manufacturing
processes
Amino
acid sequence
Protein structure
Protein structure
Mechanism of action
Inactive ingredients
Inactive ingredients
Proven efficacy, safety
Proven similarity to
reference biologic
Li E, et al. J Manag Care Spec Pharm. 2015;21: Weise M, et al. Blood. 2012;120: Lucio SD, et al. Am J Health Syst Pharm. 2013;70: FDA. Information on biosimilars
Slide credit: clinicaloptions.com

9. What Is the Naming Convention for Biosimilars?
Adalimumab-atto
Etanercept-szzs
Filgrastim-sndz
Infliximab-abda
Infliximab-dyyb
Core name
FDA-designated suffix
No recognizable meaning
4 letters
Lowercase
Slide credit: clinicaloptions.com
FDA. Nonproprietary naming of biological products: guidance for industry

10. Manufacturing of Biosimilars, Reference Biologics, and Small Molecule Generics
Small molecule generics: synthesized in chemistry labs by a well-defined set of chemical reactions; less expensive than synthesis of biologics and biosimilars[1,2]
Biosimilars and reference biologics: created in living systems by multiple steps, including cell clone selection and bulk protein production, purification, and validation[1]
Changes to manufacturing processes require FDA approval[2,3]
Biosimilars use unique cell lines and distinct manufacturing processes, thus must undergo extensive analytic evaluation to demonstrate there is no clinically meaningful difference with reference biologic[1]
1. Jeske W, et al. Drug Healthc Patient Saf. 2013;5: Mellstedt H, et al. Ann Oncol. 2008;19: Schellekens H. NDT Plus. 2009;2(suppl 1):i27-i36.
Slide credit: clinicaloptions.com

11. Can We Assure Comparable Safety and Efficacy of Biosimilars to Their Reference Biologics?
Biosimilars are designed to replicate purity, potency of reference biologics, which is anticipated to translate into clinical comparability[1]
After thorough assessment of this comparability by regulatory bodies,[2] approval of biosimilar is:
Based on preclinical/clinical studies of pharmacology, efficacy, safety, immunogenicity[2]
For specific indications only; extrapolation to other indications must be justified
Subject to postmarketing surveillance to identify any unique safety signals
1. Schellekens H, et al. Lancet Oncol. 2016;17:e502-e FDA. Scientific considerations in demonstrating biosimilarity to a reference product
Slide credit: clinicaloptions.com

12. What Is the Regulatory and Approval Pathway for Biosimilars in the US?
Abbreviated licensure pathway
Sequential, risk-based approach
Demonstration that the biosimilar and reference biologic have no clinically meaningful differences in terms of safety, purity, and potency
Efficacy/Safety of Proposed Biosimilar vs Reference Biologic
Supports Biosimilarity?
Superior No
Equivalent or noninferior
Yes
Inferior
FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry
Slide credit: clinicaloptions.com

13. What Is the Regulatory and Approval Pathway for Biosimilars in the US?
Analytical studies of 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 including assessment of toxicity
Clinical studies of PK/PD and immunogenicity
PD, pharmacodynamics; PK, pharmacokinetics.
(If uncertainty remains)
Comparative clinical studies to determine equivalence
FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry
Slide credit: clinicaloptions.com

14. Clinical Trials of New Biologics vs Biosimilars
Clinical trials aim to independently establish efficacy, safety of biologic[1]
Emphasis on large, late-phase clinical trials
Biosimilars
Clinical trials aim to demonstrate similarity to an already-approved reference biologic[2]
Stronger emphasis on analytical data[3]
Often compared with reference biologics from both US and Europe
1. Kingham R, et al. In: Wang W, et al. Biological drug products: development and strategies, first edition Alten R, et al. Semin Arthritis Rheum. 2015;44(6 suppl):S2-S8. 3. FDA. Scientific considerations in demonstrating biosimilarity to a reference product
Slide credit: clinicaloptions.com

15. How Do Clinical Development Pathways for New Biologics vs Biosimilars Compare?
Study Phase
New Biologic – 351(a)[1]
Biosimilar – 351(k)[2,3]
Preclinical and animal toxicology studies
Defines pharmacologic, toxicologic effects prior to human studies
Structural/functional analyses
Animal studies including assessment of toxicity
Phase I and II
Dose and schedule determined; immunogenicity assessed
Clinical activity and safety evaluated in given pt population
Human PK, PD, immunogenicity compared to reference biologic
Phase III
Assessed in large population to confirm therapeutic benefit
If requested by FDA because of residual uncertainty, typically designed to demonstrate equivalence or noninferiority to reference biologic
At each step, FDA determines if further studies are needed
All studies required by FDA
PD, pharmacodynamics; PK, pharmacokinetics.
1. Kingham R, et al. In: Wang W, et al. Biological drug products: development and strategies, first edition Alten R, et al. Semin Arthritis Rheum. 2015;44(6 suppl):S2-S8. FDA. 3. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry
Slide credit: clinicaloptions.com

16. Are Biosimilars and Their Reference Biologics Interchangeable?
Within the area of biosimilars, interchangeability is the ability to switch to a biosimilar from its reference biologic without prescriber consent[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]
Example switch study design:
Study design is flexible, but should include:
≥ 3 switches assures at least 2 exposure periods for each product
US-licensed reference biologic mimics clinical practice in US
Reference Biologic (US Licensed)
Study population should be pts, not healthy subjects, but does not need to be the same population used in study showing biosimilarity
B, biosimilar; RB, reference biologic.
Biosimilar RB B RB B
1. Ebbers HC, et al. GaBI Journal. 2014;3: FDA. Considerations in Demonstrating Interchangeability With a Reference Product: Guidance for Industry
Slide credit: clinicaloptions.com

17. What Biosimilars Are Currently Available in the US?
Drug Class
Approval
Date
Indications
Comparative Phase III Clinical Trial Data Leading to Approval
Filgrastim-sndz[1]
Recombinant G-CSF
2015
Prevention of severe neutropenia
PIONEER: noninferiority to prevent neutropenia in breast cancer pts on myelosuppressive chemotherapy[2]
Infliximab-dyyb[3,4]
TNF-α inhibitor
2016
Crohn’s, ulcerative colitis, RA, AS, PsA, plaque psoriasis
PLANETRA: equivalent ACR20 in RA pts[5]
PLANETAS*: equivalent ASAS20 in AS pts[6]
Infliximab-abda[7]
2017
Equivalent ACR20 in RA pts[8,9]
Etanercept-szzs[3,4]
2016; ongoing patent litigation
RA, AS, PsA, plaque psoriasis, polyarticular JIA
EGALITY: equivalent PASI75 in pts with plaque psoriasis[10]
Adalimumab-atto[11]
Crohn’s, ulcerative colitis, RA, AS, PsA, plaque psoriasis, JIA
Equivalent ACR20 in RA pts[12]
Equivalent PASI improvement in pts with psoriasis[13]
ACR20, American College of Rheumatology 20% improvement criteria; AS, ankylosing spondylitis; ASAS20, Assessment in SpondyloArthritis International Society 20% improvement criteria; G-CSF, granulocyte-colony stimulating factor; JIA, juvenile idiopathic arthritis; PASI, Psoriasis Area and Severity Index; PsA, psoriatic arthritis; RA, rheumatoid arthritis; TNF, tumor necrosis factor.
References
1. Rugo HS, et al. Cancer Treat Rev. 2016;46:73-79.
2. Blackwell K, et al. Ann Oncol. 2015;26:
3. Rutherford AI, et al. Expert Rev Clin Immunol. 2016;12:
4. Ianculescu I, et al. Curr Opin Rheumatol. 2016;28:
5. Yoo DH, et al. Ann Rheum Dis. 2013;72:
6. Park W, et al. Ann Rheum Dis. 2013;72:
7. Infliximab-abda [package insert]
8. Choe JY, et al. ACR/ARHP Abstract 2056.
9. Choe JY, et al. Ann Rheum Dis. 2017;76:58-64.
10. Griffiths CE, et al. Br J Dermatol. 2017;176:
11. Panesar K. US Pharm. 2016;41:26-29.
12. Cohen SB, et al. ACR/ARHP Abstract 2054.
13. Papp K, et al. J Am Acad Dermatol. 2017;[Epub ahead of print].
*Comparative phase I study.
Slide credit: clinicaloptions.com
References in slidenotes.

18. Extrapolation of Indications Beyond Study Populations
Biosimilar
Study Pt Population
Additional Indications Extrapolated to by FDA
Oncology
Filgrastim-sndz[1]
Neutropenia in breast cancer treatment
Neutropenia in BMT and in treatment of
nonmyeloid malignancies, AML;
severe chronic neutropenia; leukapheresis[2]
Immunology/Rheumatology
Infliximab-dyyb[3-6]
AS, RA
Crohn’s, ulcerative colitis, PsA, plaque psoriasis[7]
Infliximab-abda[8,9] RA
Crohn’s, ulcerative colitis, AS, PsA, plaque psoriasis[10]
Etanercept-szzs[11]
Plaque psoriasis
RA, AS, PsA, polyarticular JIA[12]
Adalimumab-atto[13,14]
RA, plaque psoriasis
Crohn’s, ulcerative colitis, AS, PsA, polyarticular JIA[15]
AML, acute myeloid leukemia; BMT, bone marrow transplantation; AS, ankylosing spondylitis; JIA, juvenile idiopathic arthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis.
References
1. Blackwell K, et al. Ann Oncol. 2015;26:
2. FDA. Summary review of filgrastim-sndz BLA application
3. Park W, et al. Ann Rheum Dis. 2013;72:
4. Park W, et al. Arthritis Res Ther. 2016;18:25.
5. Yoo DH, et al. Ann Rheum Dis. 2013;72:
6. Yoo DH, et al. Arthritis Res Ther. 2016;18:82.
7. FDA. AAC brief of infliximab-dyyb BLA application
8. Choe JY, et al. ACR/ARHP Abstract 2056.
9. Choe JY, et al. Ann Rheum Dis. 2017;76:58-64.
10. Infliximab-abda [package insert]
11. Griffiths CEM, et al. Br J Dermatol. 2017;176:
12. FDA. Summary review of etanercept-szzs BLA application
13. Cohen SB, et al. ACR/ARHP Abstract 2054.
14. Papp K, et al. J Am Acad Dermatol. 2017;[Epub ahead of print].
15. FDA. Summary review of adalimumab-atto BLA application
Slide credit: clinicaloptions.com
References in slidenotes.

19. Safety Studies of Biosimilars
Main Study Population
Main Safety Studies
Other Safety Studies
Filgrastim-sndz[1]
Neutropenia in breast cancer treatment
Phase III PIONEER study (n = 218)[2]
Pooled post approval studies in EU (n = 1302)[3]
Prospective study in France (n = 184)[4]
Pharmaco-epidemiologic MONITOR-GCSF study (n = 1447)[5]
Infliximab-dyyb[6]
AS, RA
Phase I PLANETAS study in AS (n = 250)[7,8]
Open-label switch extension (n = 174)[9]
Phase III PLANETRA study in RA (n = 606)[10,11]
Open-label switch extension (n = 302)[12]
Observational meta-analysis in IBD (n = 552)[13]
Infliximab-abda[14] RA
Phase III study in RA (n = 584)[15,16]
Double-blind switch extension (n = 396)[17]
Pharmacokinetic study in healthy subjects (n = 159)[18]
Etanercept-szzs[19]
Plaque psoriasis
Phase III EGALITY switch study in psoriasis (n = 531)[20]
Pharmacokinetic studies in healthy males (n = 105)[21]
Adalimumab-atto[22]
RA, plaque psoriasis
Phase III study in RA (n = 526)[23]
Phase III study in psoriasis (n = 347)[24]
Pharmacokinetic studies in healthy subjects (n = 203)[25]
AS, ankylosing spondylitis; IBD, inflammatory bowel disease; JIA, juvenile idiopathic arthritis; PsA, psoriatic arthritis; RA, rheumatoid arthritis.
References
1. Filgrastim-sndz [package insert]
2. Blackwell K, et al. Ann Oncol. 2015;26:
3. Gascón P, et al. Support Care Cancer. 2013;21:
4. Nahon S, et al. Support Care Cancer. 2016;24:
5. Gascón P, et al. Support Care Cancer. 2016;24:
6. Infliximab-dyyb [package insert]
7. Park W, et al. Ann Rheum Dis. 2013;72:
8. Park W, et al. Arthritis Res Ther. 2016;18:25.
9. Park W, et al. Ann Rheum Dis. 2017;76:
10. Yoo DH, et al. Ann Rheum Dis. 2013;72:
11. Yoo DH, et al. Arthritis Res Ther. 2016;18:82.
12. Yoo DH, et al. Ann Rheum Dis. 2017;76:
13. Komaki Y, et al. Aliment Pharmacol Ther. 2017;45:
14. Infliximab-abda [package insert]
15. Choe JY, et al. ACR/ARHP Abstract 2056.
16. Choe JY, et al. Ann Rheum Dis. 2017;76:58-64.
17. Smolen JS, et al. ACR/ARHP Abstract 2596.
18. Shin D, et al. BioDrugs. 2015;29:
19. Etanercept-szzs [package insert]
20. Griffiths CEM, et al. Br J Dermatol. 2017;176:
21. von Richter O, et al. Br J Clin Pharmacol. 2017;83:
22. Adalimumab-atto [package insert]
23. Cohen SB, et al. ACR/ARHP Abstract 2054.
24. Papp K, et al. J Am Acad Dermatol. 2017;[Epub ahead of print].
25. Kaur P, et al. Ann Rheum Dis. 2017;76:
Slide credit: clinicaloptions.com
References in slidenotes.

20. What Biosimilars Are Currently in the Pipeline in the US?
Reference Biologic
Drug Class
~ Patent
Exp. Date
Indication
Biosimilars With Phase III Clinical Trials
Trastuzumab[1-3]
HER2 inhibitor
2019
Breast cancer
CT-P6 equivalent efficacy, safety
Myl1401O accepted for FDA review
Multiple others registered/under way
Rituximab[1-3]
CD20 inhibitor
2016
Lymphoma; RA
BCD-020 equivalent PK/PD, efficacy, safety in iNHL
CT-P10 equivalent PK/PD, efficacy, safety, immunogenicity in RA
RTXM83 equivalent PK, safety in DLBCL
Bevacizumab[1-3]
VEGF inhibitor
CRC, lung, renal cancer
BCD-021 equivalent efficacy, safety, immunogenicity in NSCLC
Cetixumab[3]
EGFR inhibitor
CRC, head and neck cancer
1 under way
Adalimumab[2-4]
TNF-α inhibitor
2022*
Autoimmune diseases
BI accepted for FDA review
Infliximab[2-4]
2018*
Multiple registered/under way
Filgrastim[2,5]
rG-CSF
2013
Neutropenia
Gastrofil accepted for FDA review
Registered trial for MK-4214 under way
Pegfilgrastim[2,5]
2015
2 pegfilgrastim biosimilars accepted for FDA review, including CHS-1701
Epoetin alfa[2,5]
r-EPO
Anemia
Retacrit submitted to FDA, multiple others registered/under way
CRC, colorectal cancer; DLBCL, diffuse large B-cell lymphoma; EPO, erythropoietin; iNHL, indolent non-Hodgkin lymphoma; NSCLC, non-small-cell lung cancer; PD, pharmacodynamic; PK, pharmacokinetic; rG-CSF, recombinant granulocyte colony-stimulating factor; RA, rheumatoid arthritis; TNF, tumor necrosis factor.
References:
1. Rugo HS, et al. Cancer Treat Rev. 2016;46:73-79.
2. Stevenson JG, et al. Ann of Pharmacotherapy. 2017;[Epub ahead of print].
3. Panesar K. US Pharm. 2016;41:26-29.
4. Goel N, et al. Rheumatology. 2017;56:
5. Derbyshire M. GaBI Journal. 2015;4:
*Ongoing patent litigation.
Slide credit: clinicaloptions.com
References in slidenotes.

21. Explaining Biosimilars to Pts: Potential Topics
Use of biologics in the specific disease setting
Definition of a biosimilar
Totality of evidence required to demonstrate similar safety and efficacy of the biosimilar to its reference biologic
Simplified explanations
How the biosimilar is administered and any device that may be used
Insurance coverage and out-of- pocket cost
How decreased cost of biosimilars can lead to increased access to more expensive biologics
Available pt support services
Identity of the manufacturer
May be familiar to pt and promote acceptance
Slide credit: clinicaloptions.com
Jacobs I, et al. Patient Prefer Adherence. 2016;10:

22. Reimbursement of Biosimilars by Payers: Medicare
Medicare Part B: reimbursement slightly higher than ASP[1]
Payment for biosimilars is based on ASP plus 6% of ASP of reference biologic
Medicare Part D: new biosimilars treated like new branded drugs from formulary review and pt cost-sharing standpoint[2]
Biosimilars ineligible for 50% coverage gap discount
Biosimilar and reference biologic will not be considered different drugs for purposes of satisfying Part D formulary requirement for 2 distinct drugs per category/class
ASP, average sale price.
1. Centers for Medicare & Medicaid Services. Part B biosimilar biological product payment and required modifiers Centers for Medicare & Medicaid Services. Part D requirements for biosimilar follow-on biological products
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23. Reimbursement of Biosimilars by Payers: Commercial
Commercial payer coverage will likely be based on:
Cost differential
Interchangeability designation
Nature of FDA approval
Therapeutic area
Medical community
Centers for Medicare & Medicaid Services
Pt community
Slide credit: clinicaloptions.com
Felix AE, et al. GaBI Journal. 2014;2:

24. Go Online for More CCO Coverage of Biosimilars!
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