1. Expert Answers to Frequently Asked Questions About Biosimilars

2. About These Slides
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3. Faculty
Robert M. Rifkin, MD, FACP 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.

4. Faculty Disclosures
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.

5. 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]
FDA, US Food and Drug Administration.
Slide credit: clinicaloptions.com
1. FDA. Information on biosimilars Cornes P. Target Oncol. 2012;7:57-67.

6. How Do Biosimilars vs Small Molecule Generics Compare?
Characteristic
Biosimilar
Generic
Structure
Large, complex biological 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[5]
Manufacturing process[2]
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[3]
Demonstrate similar safety, purity, potency, and efficacy[4]
Abbreviated New Drug Application[5]
Demonstrate bioequivalence[1]
FDA, US Food and Drug Administration.
1. Li E, et al. J Manag Care Spec Pharm. 2015;21: Jeske W, et al. Drug Healthc Patient Saf. 2013;5: FDA. Information for industry (biosimilars) FDA. Information on biosimilars FDA. What are generic drugs? 2015.
Slide credit: clinicaloptions.com

7. 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
FDA, US Food and Drug Administration.
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

8. 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]
FDA, US Food and Drug Administration.
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

9. 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
FDA, US Food and Drug Administration.
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

10. What Is the Regulatory and Approval Pathway for Biosimilars in the United States?
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
FDA, Federal Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics.
FDA. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry
Slide credit: clinicaloptions.com

11. What Is the Regulatory and Approval Pathway for Biosimilars in the United States?
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
FDA, Federal Drug Administration; 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

12. 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
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. 3. FDA. Scientific considerations in demonstrating biosimilarity to a reference product
Slide credit: clinicaloptions.com

13. 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
FDA, US Food and Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics.
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. Scientific considerations in demonstrating biosimilarity to a reference product: guidance for industry
Slide credit: clinicaloptions.com

14. 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; FDA, US Food and Drug Administration; RB, reference biologic.
Biosimilar RB B RB B
1. Ebbers HC, et al. GaBI Journal. 2014;3:88-93.
2. FDA. Considerations in Demonstrating Interchangeability With a Reference
Product: Guidance for Industry
Slide credit: clinicaloptions.com

15. What Biosimilars Are Currently Available in the United States?
Drug Class
Approval
Date
Indications
Comparative Phase III Clinical Trial Data Leading to Approval
Oncology
Filgrastim-sndz[1]
Recombinant G-CSF
2015
Prevention of severe neutropenia
PIONEER: noninferiority to prevent neutropenia in breast cancer pts on myelosuppressive chemotherapy[2]
Immunology/Rheumatology
Infliximab-dyyb[3,4]
TNF-α inhibitor
2016
Crohn’s, ulcerative colitis, RA, AS, PsA, plaque psoriasis
PLANTERA: equivalent ACR20 in RA pts[5]
PLANETAS: equivalent ASAS20 in AS pts[6]
Extrapolated to other indications
Etanercept-szzs[3,4]
2016; ongoing patent litigation
RA, AS, PsA, plaque psoriasis, polyarticular JIA
EGALITY: equivalent PASI75 in pts with plaque psoriasis[7]
Adalimumab-atto[8]
Crohn’s, ulcerative colitis, RA, AS, PsA, plaque psoriasis, JIA
Equivalent ACR20 in RA pts[9]
Equivalent PASI improvement in pts with plaque psoriasis[10]
ACR20, American College of Rheumatology 20% improvement criteria; AS, ankylosing spondylitis; ASAS20, Assessment in SpondyloArthritis International Society 20% improvement criteria FDA, US Food and Drug Administration; 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. Griffiths CE, et al. Br J Dermatol. 2016;[Epub ahead of print].
8. Panesar K. US Pharm. 2016;41:26-29.
9. Cohen SB, et al. ACR/ARHP Abstract 2054.
10. Papp K, et al. EADV 2014.
Slide credit: clinicaloptions.com
References in slidenotes.

16. What Biosimilars Are Currently in the Pipeline in the United States?
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*
SB2 accepted for FDA review
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; G-CSF, granulocyte colony-stimulating factor; FDA, US Food and Drug Administration; iNHL, indolent non-Hodgkin lymphoma; PD, pharmacodynamic; PK, pharmacokinetic; r, recombinant; RA, rheumatoid arthritis; TNF, tumor necrosis factor; EPO, erythropoietin.
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.

17. 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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18. 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
FDA, US Food and Drug Administration.
Slide credit: clinicaloptions.com
Felix AE, et al. GaBI Journal. 2014;2:

19. Go Online for More CCO Coverage of Biosimilars!
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