Objectives Compare and contrast the terms biosimilar and biologic - - PDF document

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Biosimilars: What Prescribers Need To Know

Diana Webber, DNP, APRN-CNP April 2018

Objectives

• Compare and contrast the terms biosimilar and

biologic reference product regarding structure, manufacturing, regulatory pathway, and clinical properties.

• Discuss potential safety concerns with biosimilars
• Describe current FDA policy related to

prescribing biosimilar agents.

• Evaluate if biosimilar agents are appropriate for

select patients based on risks/benefits, disease/treatment-related factors, and patient preferences.

Outline

A. Definition “biologic” drug product

i. Comparison biologic with small-molecule chemical drug ii. Nomenclature biologic products

B. Definition “biosimilar” drug product

i. Comparison biosimilar to generic small-molecule drug ii. Comparison biosimilar to biologic reference product iii. General principles of biosimilarity

C. Biosimilar safety

i. Immunogenicity ii. Interchageability & Extrapolation

D. FDA Policy and Prescriber Concerns

i. Approval process ii. Nomenclature iii. Prescriber Concerns

E. Prescribing Scenario

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Quiz Time!

1. Small-molecule chemical drugs and biologics are used to treat a variety of diseases. Do you think that there is a significant difference between a small-molecule drug and a biologic agent? A. YES B. NO 2. In which ways do biosimilars and generic chemical drugs resemble each other? A. Both involve complex manufacturing processes, and it is impossible to ensure identical copies B. Both are stable products, not sensitive to external conditions C. Both products are non-immunogenic D. Biosimilars do not resemble generic chemical drugs

Definition “Biologic”

• Biological product
• Biopharmaceutical examples:

– Botox – Herceptin – Enbrel – Insulin analogs

• Biologics 20-35% of new drugs in pipeline
• Source materials
• Recombinant DNA

https://www.ecfr.gov/cgi-bin/text- idx?SID=a3931adb89f6a292d67a7c48340f5b1a&mc=true&node=se21.7.600_13&rgn=div8

Identification and isolation of the gene of interest: https://www.youtube.com/watch?v=a Yhf-FXpoYs

Development of a Biologic product

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Chemical vs Biologic Drug

Chemical versus Biologic Drug Chemical (e.g. aspirin) Biologic (e.g. monoclonal antibody) Low molecular weight High molecular weight Well-defined, homogeneous chemical structure Complex, heterogeneous structure Produced by chemical synthesis; predictable chemical process; can make identical copies Produced in living cell culture; difficult to control process; impossible to ensure identical copy Stable Unstable, sensitive to external conditions Mostly non-immunogenic Immunogenic Li, et al. (2015); CCO (2017), clinicaloptions.com

Chemical vs Biologic Drug

Kozloski, 2011

Biosimilars

• Reverse-engineered copies of FDA-

approved biologic agents no longer under patent protection

• Biologic products designed to mimic

existing, approved biologic agents

• Similar but not identical to reference

biologic agent

• Not “generic” for reference drug

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Biosimilar Definition

• A biologic product that is

– “highly similar to the reference product notwithstanding minor differences in clinically inactive components” – “there are no clinically meaningful differences between the reference product and the biologic product in terms of the safety, purity, and potency

• f the product.”

Biologics Price Competition and Innovation (BCPI) Act of 2009

Biosimilar Not Generic

Property Generic Chemical Drug Biosimilar Structural complexity Small, simple, reproducible molecule Large, complex, biologic molecule Comparison to Reference Agent

• Identical active

ingredients

• Same dosage, route of

administration, bioequivalence, strength, purity

• Same amino acid sequence
• May differ in some

parameters

• Higher potential

immunogenicity Manufacturing Process

• Chemical synthesis
• Predictable set

chemical reactions

• Created in living systems
• Unique cell lines &

production steps from reference product FDA-approval Process

• Abbreviated New Drug

Application

• Demonstrate

bioequivalence

• Biosimilar Biologics License

Application (abbreviated)

• Demonstrate similar safety,

purity, potency, efficacy Li, et al. (2015); CCO (2017)

Biosimilar Not Generic

Property Generic Chemical Drug Biosimilar

Immunogenic potential Less likely; allergic reactions can occur Possible; requires testing and monitoring Interchangeability with reference agent Allowed by FDA if standards

• f purity and bioequivalence

have been met Only when a FDA “higher standard of interchangeability” has been met Automatic substitution Generally allowed, depending on state law and prescriber preference FDA guidance pending Nomenclature Name is generally the same as the International Non- proprietary Name (INN) FDA proposes unique nomenclature that shows relationship but distinction from reference product Cost Much less than branded product Varies: 15-90% less than reference product; greater cost savings outside of U.S.

Rak Tkaczuk & Jacobs (2014); Kay, et al. (2018); Blackstone & Joseph (2013); ACR (2016)

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Slide credit: clinicaloptions.com

What Features Do Biosimilars Share With Their Reference Biologics?

Li E, et al. J Manag Care Spec Pharm. 2015;21:532-539. Weise M, et al. Blood. 2012;120:5111-5117. Lucio SD, et al. Am J Health Syst Pharm. 2013;70:2004-2017. FDA. Information on biosimilars. 2016.

Reference Biologic Biosimilar

Amino acid sequence Manufacturing processes Host cell line Protein structure Manufacturing processes Host cell line Inactive ingredients Proven efficacy, safety Proven similarity to reference biologic Mechanism

• f action

Protein structure Inactive ingredients https://www.clinicaloptions.com/Immunology/Treatment%20Updates/Biosimilar%20Perspectives.aspx

General Principles Biosimilarity

• Biosimilar must demonstrate no clinically

significant difference from reference product

– Robust analytical, toxicologic, PK/PD, and immunogenicity studies compared to reference product – Smaller comparative effectiveness clinical trials, which must be conducted in patients with a disease for which the reference product is licensed – No need to demonstrate efficacy in all indications

• No differences in safety/efficacy between

approved biosimilar and reference product

– Same mechanism of action – Same route of administration, dosage form, dosage strength

Slide credit: clinicaloptions.com

General Principles Biosimilarity

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Critical Attributes for Biosimilarity

Lot-to-lot variability of critical quality attributes must be assessed and controlled to ensure consistent product quality High-Quality Biosimilar Not a Biosimilar

Similar Acceptable differences Difference with critical

• r unknown impact

Process- related impurities Higher

• rder

structure Biological function Particles and aggregates Primary structur e Product purity Stability

• 95 attributes similar
• 2 acceptable

differences

• 0 critical differences
• 87 attributes similar
• 7 acceptable

differences

• 3 critical differences

Process- related impurities Higher

• rder

structure Biological function Particles and aggregates Product purity Stability General properties and excipients Primary structur e Slide credit: clinicaloptions.com

• FDA. Overview of biosimilar products. 2016.

General properties and excipients

Terms Related to Safety

• Interchangeability: “designation that allows a

biosimilar agent to be substituted for its reference product with prescriber input.”

• Substitution: “interchange or replacement of a

biosimilar agent with its reference product by someone other than the prescribing health professional.”

• Switch: “therapeutic transition from a reference

product to a biosimilar agent or vice versa, based

• n prescriber decision.”

Dorner & Kay (2015)

Biosimilar Safety

• Biosimilar has same risk profile as its

reference product

• Potential adverse reactions due to variations

in manufacturing of reference biologic and biosimilar

• Potential risk associated with

interchageability and automatic switching by pharmacy

• Potential risk associated with extrapolation
• f data

Khraishi, et al. (2016)

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“Switching”

NOR-SWITCH study (2017)

– 52-week randomized, double-blind Phase 4 trial in pts with RA, SpA, CD, Ps, PsA, or UC; stable on infliximab for ≥ 6 mos – Primary endpoint: disease worsening during 52-wk follow-up – Infliximab (n=202); infliximab-dyyb (n=206) – Result: switching from infliximab to infliximab-dyyb non-inferior to continued treatment with infliximab

EGALITY trial (2017)

Jӧrgensen, et al. (2017)

Extrapolation

Examples:

– Adalimumab (Humira): approved for RA, Ps, PsA, AS, CD, UC – Adalimumab-atta (Amjevita): same indications – Rituximab (Rituxin): approved for non- Hodgkin lymphoma, CD-20 + CLL, moderate- severe RA – GP2013 (Rixathon- biosimilar rituximab): license application accepted by FDA 9/2017

Quiz Time!

1. According to FDA guidance, what types of studies serve as the beginning or “foundation” for the stepwise development

• f a biosimilar?

A. Structure/function B. Toxicity C. Immunogenicity D. Clinical efficacy and safety

2. A biosimilar approved by the FDA may be substituted without the intervention of the provider who prescribed the reference product under what circumstances?

A. Any biosimilar with FDA approval may be substituted for approved indications. B. If allowed by state substitution laws C. If approved as interchangeable by the FDA and allowed by state laws D. Substitution rules vary depending on therapeutic class

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FDA Approval Process

• 351(k) abbreviated approval

pathway

• Standards for approval

– FDA goal: to establish biosimilarity with the reference product, not to independently establish safety and

• effectiveness. Biosimilar can rely on

safety/efficacy data from the reference product

Stepwise Approach

The foundation for the approach is the Analytical Studies. Then a stepwise approach evaluates “residual uncertainty” at each step

FDA Approved Biosimilars

Drug Name Approval Class *Zarxio (filgrastim-sndz) 3/2015 Colony stim factor *Inflectra (infliximab-dyyb) 4/2016 TNF-inhibitor Erelzi (etanercept-szzs) 8/2016 TNF-inhibitor Amjevita (adalimumab-atta) 9/2016 TNF-inhibitor *Renflexis (infliximab-abda) 5/2017 TNF-inhibitor Cyltezo (adalimumab-adbm) 8/2017 TNF-inhibitor Mvasi (bevacizumab-awwb) 9/2017 VEGF-inhibitor Hemlibra (emicizumab-kxwh) 11/2017 mAb Ogivri (trastuzamab-dkst) 12/2017 HER2/neu-inhibitor Ixifi (infliximab-qbtx) 12/2017 TNF-inhibitor

FDA Approved Biosimilar Products as of 12-2017

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2018 Biosimilar HCPCS Codes

Biosimilar HCPCS Code Product Brand names Corresponding Required Modifier Q5101 Injection, Filgrastim (G-CSF), Biosimilar, 1 microgram Zarxio ZA - Novartis/Sandoz Q5102 Injection, infliximab, biosimilar, 10 mg Inflectra ZB - Pfizer/Hospira Q5102 Injection, infliximab, biosimilar, 10 mg Renflexis ZC –Merck/Samsung Bioepis CMS Biosimilar Product-HCPCS Payment Codes

Nomenclature

• Same non-proprietary name as reference

product (core name) but with a 4-letter suffix

– Randomly generated – Devoid of meaning – Only lower-case letters – Attached to core name with a hyphen – Free of legal barriers that would restrict usage

• Examples: infliximab (Remicade)

– Infliximab-abda (Renflexis) – Infliximab-dyyb (Inflectra) – Infliximab-qbtx (Ixifi)

Prescriber Concerns

• Interchangeability/Substitution without

consent of prescriber The Purple Book

• Notification of patient and prescriber when

substitution occurs

• Cost: CMS biosimilar payment changes

may encourage use in Medicare patient population

• How to introduce biosimilars into your

practice

CMS 2018 Revisions to Part B Payments (p.53348-53349): https://www.gpo.gov/fdsys/pkg/FR-2017-11-15/pdf/2017-23953.pdf

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Introducing Biosimilars into Practice

Potential Scenarios:

• Gradual introduction of biosimilars only in pts

newly starting a biologic

• Instant switching to biosimilars for pts currently

receiving a biologic

• Switching due to loss of response or adverse

events with a biologic

• Switching between the biosimilar and the

reference drug on an alternating basis, depending on pharmacy supply and drug product availability

Scenario

• 44 y/o Caucasian female; seropositive RA x 8 years
• Initial course of therapy aggressive. Good control x3

years on this combination of meds:

– Methotrexate (non-biologic) – Hydroxychloroquine (non-biologic) – Etanercept (biologic TNF inhibitor)

• Received letter from insurance provider

recommending she switch to biosimilar TNF inhibitor

• She would like to decrease her out-of-pocket

insurance costs, but she is concerned about the safety and efficacy of the biosimilar

• She asks you a few questions…

Patient Questions

• What is a biosimilar?
• Do biosimilars work as well as the

reference product?

• What are the risks associated with

biosimilar use?

• If the etanercept is working, why should I

change?

• Do you recommend that I switch to the

biosimilar?

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For More Information

• https://www.fda.gov/drugs/developmenta

pprovalprocess/howdrugsaredevelopeda ndapproved/approvalapplications/therap euticbiologicapplications/biosimilars/

• Search: FDA Biosimilars safe effective

treatment options

Questions? References

• American College of Rheumatology (2016). Position statement:
• Biosimilars. Presented by Committee on Rheumatologic Care.

https://www.rheumatology.org/Portals/0/Files/Biosimilars-Position- Statement.pdf

• Biologics Price Competition and Innovation Act of 2009. United

States Code, 111th Congress. 2nd Session ed. United States, 2010: 804-821.

• Blackstone, E.A., Joseph, P.F. (2013). The economics of
• biosimilars. American Health Drug Benefits, 6(8), p. 469-478.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4031732/

• Clinical Care Options (2017). Slidesets: Immunology- Biosimilars.

Retrieved from clinicaloptions.com https://www.clinicaloptions.com/Immunology/Slidesets.aspx

• Chow, S., Song, F., Bai, H. (2016). Analytical similarity assessment

in biosimilar studies. The AAPS Journal, 18(3), p. 670-677. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5256601/

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References

• Dörner, T., Kay, J. (2015). Biosimilars in rheumatology: current

perspectives and lessons learnt. Nature Reviews Rheumatology, 11 (12), p. 713-724. https://www.researchgate.net/profile/Jonathan_Kay/publication/2810 96426_Biosimilars_in_rheumatology_Current_perspectives_and_le ssons_learnt/links/56658c2308ae4931cd623f1a/Biosimilars-in- rheumatology-Current-perspectives-and-lessons-learnt.pdf

• FDA (2017). Biosimilar product regulatory review and approval.

Retrieved https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrug sareDevelopedandApproved/ApprovalApplications/TherapeuticBiolo gicApplications/Biosimilars/ucm580429.htm

• Fluhmann, B., et al. (2015). Non-biological complex drugs (NBCDs)

and their follow-on versions: time for an editorial section. Genetics and Biosimilars Initiative Journal, 4(4): 167-70. Retrieved from http://gabi-journal.net/non-biological-complex-drugs-nbcds-and- their-follow-on-versions-time-for-an-editorial-section.html

References

• Hoffman, M., Barry, J. (2018). U.S. biosimilars: The hope and the
• hype. Back Bay Whitepaper U.S. Biosimilars 2018: Opportunities

and Challenges. Retrieved from https://bblsa.com/documents/Back- Bay-US-Biosimilars-2018.pdf

• Hollander, P., Spellman, C.W. (2016). Preparing for the wave of the

future: Biosimilars. CME: The France Foundation. Retrieved from http://www.biosimilarscme.org/content/Preparing_for_the_Wave_of_ Biosimilars_ebook.pdf

• Jӧrgensen, K.K., Olsen, I.C, Lorentzen, M., Bolstad, N.,

Haavardsholm, E. A., Lundin, K.E.A….Kvient, T.V. (2017). Switching from originator infliximab to biosimilar CT-P13 compared with maintained treatment with originator, infliximab (NOR-SWITCH): A 52- week, randomized, double-blind, non-inferiority trial. The Lancet. Published online May 11, 2017 http://dx.doi.org/10.1016/S0140- 6736(17)30068-5

References

• Kay, J., Schoels, M.M., Dorner, T., Emery, P., Kvien, T. K., Smolen,

J.S., Breedveld, F.C. (2018). Consensus-based recommendations for the use of biosimilars to treat rheumatologic diseases. Annals Rheumatological Disease, 77, p. 165-174. https://connect.ouhsc.edu/content/annrheumdis/77/2/,DanaInfo=ard.b mj.com+165.full.pdf

• Khraishi, M., Stead, D., Lukas, M., Scotte, F., Schmid, H. (2016).

Biosimilars: A multidisciplinary perspective. Clinical Therapeutics, 38(5), p. 1238-1249. https://www.sciencedirect.com/science/article/pii/S014929181630092 3

• Kozlowski, S. Woodcock, J., Midthun, K., Behrman Sherman, R.

(2011). Developing the nation’s biosimilars program. New England Journal Medicine, 365, p. 385-388. http://www.nejm.org/doi/full/10.1056/NEJMp1107285

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References

• Li, E.C., Ramanan, S., Green, L. (2015). Pharmacist substitution
• f biologic products: Issues and considerations. Journal of

Managed Care and Specialty Pharmacy, 21, 532-539. https://www.jmcp.org/doi/pdf/10.18553/jmcp.2015.21.7.532

• Lybecker, K.M. (2016). The biologics revolution in the production
• f drugs. Fraser Institute.

https://www.fraserinstitute.org/sites/default/files/biologics- revolution-in-the-production-of-drugs.pdf

• Rak Tkaczuk, K. H., Jacobs, I.A. (2014). Biosimiliars in oncology:

From development to clinical practice. Seminars in Oncology, 41(S3), S3-12. Retrieved http://www.seminoncol.org/article/S0093-7754(14)00056- 6/fulltext

References

• U.S. Department of Health and Human Services, FDA, CDER,

CBER (2017). Non-proprietary naming of biological products: Guidance for industry. https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegu latoryInformation/Guidances/UCM459987.pdf