Granulocyte-Colony Stimulating Factor Biosimilars

An Update for Frontline Oncology Practitioners This educational activity is jointly accredited for nurses and pharmacists and is supported by an independent educational grant from , Inc. Faculty

Sandra Cuellar, PharmD, BCOP Clinical Associate Professor, Pharmacy Practice University of Illinois at Chicago College of Pharmacy Oncology Resident Director, Ambulatory Pharmacy Services UI Health Chicago, IL

Dr. Cuellar is a Clinical Associate Professor in the Department of Pharmacy Practice at the University of Illinois at Chicago (UIC) College of Pharmacy. Dr. Cuellar is a Board-Certified Oncology Pharmacist and works as a clinical oncology pharmacist at UI Health. She serves as the oncology residency program director, member of the DSMC, and vice-chair of the IRB. She is an invited lecturer, providing numerous national and international presentations on cardio-oncology, supportive care oncology, biosimilars, and oncology therapeutics. Faculty

Kristi Orbaugh, MSN, RN, NP, AOCN Adult Nurse Practitioner Community Hospital Oncology Physicians Indianapolis, IN

Kristi Orbaugh has spent her entire career in the oncology field. She received her undergraduate degree from Purdue University and her master’s degree from Indiana University—Purdue University of Indianapolis. She works as a nurse practitioner at Community Hospital Cancer Center North, which is an affiliate of MD Anderson. She has published several oncology-related articles. Ms. Orbaugh is passionate about oncology and enjoys presenting and providing oncology education on regional, national, and international levels. Disclosures

Dr. Cuellar has disclosed that she has served as a consultant for Coherus Biosciences and Pfizer, Inc.

Ms. Orbaugh has disclosed that she has served on the Speaker’s Bureau for Bristol-Myers Squibb, Coherus Biosciences, Dova, Immunomedics, Lilly, Morphos, Pfizer, Inc. and Rigel.

The clinical reviewer, Megan May, PharmD, BCOP has no actual or potential conflict of interest in relation to this program.

Susanne Batesko, BSN, RN, Robin Soboti, RPh, and Susan R. Grady, MSN, RN, as well as the planners, managers, and other individuals, not previously disclosed, who are in a position to control the content of Postgraduate Healthcare Education (PHE) continuing education activities hereby state that they have no relevant conflicts of interest and no financial relationships or relationships to products or devices during the past 12 months to disclose in relation to this activity. PHE is committed to providing participants with a quality learning experience and to improve clinical outcomes without promoting the financial interests of a proprietary business. Joint Accreditation Statement

In support of improving patient care, this activity has been planned and implemented by the Postgraduate Institute for Medicine and Postgraduate Healthcare Education. Postgraduate Institute for Medicine is jointly accredited by the Accreditation Council for Continuing Medical Education (ACCME), the Accreditation Council for Pharmacy Education (ACPE), and the American Nurses Credentialing Center (ANCC), to provide continuing education for the healthcare team.

Continuing Nursing Education The maximum number of hours awarded for this Continuing Nursing Education activity is 1.25 contact hours. Pharmacotherapy contact hours for Advanced Practice Registered Nurses will be designated on your certificate.

Pharmacy Accreditation Postgraduate Healthcare Education, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. UAN: 0430-9999-21-003-H01-P Credits: 1.25 hour (0.125 CEU) Type of Activity: Application Learning Objectives

• Discuss the current data supporting short- and long-acting granulocyte-colony stimulating factor (G-CSF) use in prevention of febrile neutropenia and during the COVID-19 era • Formulate practical approaches to incorporating G-CSF biosimilars into healthcare system formularies and/or clinical pathways • Recognize the need for educational interventions that will improve healthcare providers’ understanding of G-CSF biosimilars use in cancer supportive care G-CSF Biosimilars Overview G-CSF Biosimilars Overview

• Definition of a biosimilar • Brief overview of the approval process • Short- and long-acting G-CSF biosimilars currently available • Similarities and differences of currently approved biosimilars and originator products A Bio-What? Biosimilars

• Biosimilar: a biologic product highly similar to a previously FDA-licensed biologic product that has been previously licensed by the FDA • Licensed product is referred to as the “reference product” • Derived from living organisms or living cells • Larger and much more complex than small molecule medications • Variability is allowed • No clinically meaningful difference in safety, potency, or purity

Cook JW, et al. Ther Adv Med Oncol. 2019;11:1758835918818335. Biosimilar Approval Process

• Demonstrate there are no clinically meaningful differences between reference product and biosimilar • Detailed analytical and structural testing • FDA reviews evidence from comparative analytical, nonclinical, clinical pharmacology, and clinical studies in a stepwise approach • Studies compare purity, potency, and efficacy to the reference product • Pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity studies • Human studies initially conducted in healthy subjects to reduce PK/PD variability

Waller CF, Friganovic A. Future Oncol. 2020;16(25):1931-1939.;Lyman GH, et al. J Clin Oncol. 2018;36(12):1260-1265. Available G-CSF Biosimilars

Short-acting FDA Approved Zarzxio (-sndz) March 2015 Nivestym (filgrastim-aafi) July 2018

Pegylated, long-acting Fulphila (-jmdb) June 2018 Udenyca (pegfilgrastim-cbqv) November 2018 Ziextenzo (pegfilgrastim-bmez) November 2019 Nyvepria (pegfilgrastim-apgf) June 2020

European Medicines Agency has approved 8 filgrastim and 5 pegfilgrastim biosimilars

Frazer MB, et al. J Oncol Pharm Pract. 2020;26(3 suppl):3-10. Similarities and Differences

• Tbo-filgrastim (Granix) is not considered a biosimilar • Approved as an original biologic prior to development of FDA biosimilar process • Similar to the originator product, but a more limited indication • ASCO and NCCN guidelines • Some G-CSF biosimilars (i.e., filgrastim-aafi, filgrastim-sndz) have the same indications as the originator product • Other biosimilars have more limited indications • Filgrastim (Neupogen) has the only indication for acute radiation syndrome

Wicherska-Pawlowska K, et al. J Clin Apher. 2020;35(1):4-8.; NCCN Clinical Practice Guidelines in Oncology. Hematopoietic Growth Factors. Version 2.2020– January 27,2020.; https://www.asco.org/practice-policy/policy-issues-statements/asco-in-action/media-issue-brief-biosimilars Discussion G-CSF Reference Products and Biosimilars in Supportive Care Supportive Care with Biosimilars

• Febrile neutropenia prevention • Neutropenia treatment • Mobilization for hematopoietic stem cell transplantation • Neutrophil recovery post-hematopoietic stem cell transplantation • Coronavirus disease (COVID)-19 Neutropenia Prevention and Treatment

• Neutropenia is a significant threat for patients with cancer • Affects approximately 50% of patients undergoing myelosuppressive chemotherapy • Febrile neutropenia prevention • NCCN recommends G-CSF for all patients receiving chemotherapy regimens deemed high risk (>20%) • Goal is to • Shorten length of neutropenia • Decrease hospitalization risk • Decrease length of hospitalization

Smith TJ, et al. J Clin Oncol. 2015;33(28):3199-3212.; NCCN Clinical Practice Guidelines in Oncology. Hematopoietic Growth Factors. Version 2.2020– January 27,2020. Mobilization and Neutrophil Recovery

• G-CSF originators and biosimilars can be used for: • Stem cell mobilization enhancement for HSCT • Neutrophil recovery post-HSCT • Post-treatment prophylaxis • Reduce number of days required for neutrophil engraftment post-treatment • Reduce antibiotic therapy and hospitalization length

HSCT=hematopoietic stem cell transplantation Pahnke S, et al. Bone Marrow Transplant. 2019;54(6):858-866. Impact of COVID-19 Pandemic

• NCCN extended recommendation for prophylactic G-CSF • Intermediate risk for FN (10% to 20%). • May also be appropriate in patients receiving low-risk regimens (<10%) • Multiple comorbidities or age puts them at higher FN risk

https://www.nccn.org/covid-19/pdf/HGF_COVID-19.pdf Caution with COVID-19

• Consider discontinuing/avoiding G-CSF use in patients with • Respiratory symptoms • Respiratory infection • Confirmed or suspected COVID-19 • Decrease the risk of increased pulmonary inflammation • Decrease hypothetical risk of increased inflammatory cytokines • Associated with possible adverse outcomes

https://www.nccn.org/covid-19/pdf/HGF_COVID-19.pdf Discussion Biosimilar Integration: Issues & Challenges Disrupting the Pharmaceutical Biologic Ecosystem

Biologics are the cornerstone of cancer treatment

Biologics are expensive and costs are increasing progressively

Biosimilars increase market competition without compromising efficacy or safety University Hospitals Health System in Ohio •$>450,000 annualized cost avoidance implementation of biosimilar filgrastim-sndz

Cost Kar I., et al. ASHP Midyear 2020 Poster Presentation. December 7, 2020. Savings: Real World Kalispell Regional Medical Center in Montana •Biosimilar peg-filgrastim-cbqv saved medical center $350,000 (12 months)

Easley H, Klotz M. ASHP Midyear 2020 Poster Presentation. December 8, 2020. Variables to Successful Biosimilar Integration into Health Care System

Manufacturing & FDA Regulatory Development of Pathway Biosimilar Products

Biosimilar Degree of Efficacy & Safety Pharmacoeconomic Integration into Benefit Oncology Practice

Scientific Community: Healthcare Payer & Institutional Data Evaluation, Professional & Patient Acceptance Guidelines, Position Acceptance Statements

Dolan C. Am J Manag Care. 2018;24(suppl 11):S237-S243 Biosimilar Education: Efficacy & Safety

• Understanding biosimilar development program • FDA approval based on totality of evidence • Clinical data • Switching studies • Clinical trial design • Data in curative versus non-curative setting • Endpoints (e.g., response rates, progression free survival) • Extrapolation indications • Safety • Immunogenicity Provider Awareness

Cohen, et al. conducted a survey from November 2015 to January 2016 among specialty physicians

Objective was to assess current physician awareness, knowledge, and perceptions regarding biosimilars

19 question survey created by Biosimilars Forum

Administered by an independent 3rd party

Cohen H, et al. Adv Ther. 2017;33(12):2160-2172.. Challenges: Provider Awareness

Which of the following statements are true when the FDA approves a biosimilar? Medical- Hematologist- Oncologists Oncologists The biosimilar will have equivalent efficacy 67.5% 69.0% as its originator brand counterpart. The biosimilar will be at least as safe as 66.5% 62.5% its originator brand counterpart. A pharmacist will be allowed to substitute a biosimilar for the originator brand 18.5% 17.5% counterpart without asking the prescriber. The biosimilar will always be approved for all of the indications of use of the 28.5% 37.0% originator brand counterpart.

Cohen H et al. Adv Ther. 2017;33(12):2160-2172. Variables to Successful Biosimilar Integration into Health Care System

Manufacturing & FDA Regulatory Pharmacovigilance Development of Pathway Biosimilar Products

Biosimilar Degree of Efficacy & Safety Pharmacoeconomic Integration into Benefit Oncology Practice

Scientific Community: Healthcare Payer & Institutional Data Evaluation, Professional & Patient Acceptance Guidelines, Position Acceptance Statements

Dolan C. Am J Manag Care. 2018;24(suppl 11):S237-S243 Calculating Pharmacoeconomic Benefit

Reference Product Cost & Revenue (Inpatient/Outpatient) vs. Biosimilar Payer Mix

AC +/- % Group Purchasing Organizations

7 8 9 340B

4 5 6 Rebate Arrangements Patient Out-of-Pocket Costs

1 2 3 X Biosimilar Reimbursement 0 . Manufacturers Reference Biosimilar Challenges with biologic Financial Analysis Price competition • G-CSF Multiple Purchase price Rebate Biosimilars • Pegfilgrastim

Payment rates & utilization management • Medicare, Medicaid Providers Insurers Multiple Payer • Commercial Insurances Policies Prescribing decisions Cost Product • Onpro Device sharing Premiums Administration Patients Differences Onpro Pegfilgrastim vs. Biosimilar Pegfilgrastim

Increased convenience • Reported device failure Reduced drug administration burden on rate 1% to 10% healthcare system • May result in higher costs • Patient preference • Insurance coverage • Medicare • Medicaid • Commercial Device failures Higher cost

McBride A, et al. J Med Econ. 2020;23(1):28-36.; Bittner B, et al. BioDrugs. 2018;32(5):425-440. Pivotal Initial Steps: Biosimilar Integration

Pharmaco- HCP Biosimilar economic Benefit Acceptance

Formulary Preparation Discussion Best Practices for Biosimilar Integration P&T Committee: Gateway to Biosimilar Adoption

• Evaluate safety, efficacy, and economic value of medication use in an institution • Identify institution physician/pharmacy champion • Determine current biologic utilization • Forecast potential economic benefit of biosimilars • Resource for scientific review of biosimilars • Biosimilar implementation strategy • Resources • GPO may have side-by-side comparisons of biosimilars • Facts and Comparisons Formulary service • Drug information monograph service P&T=Pharmacy & Therapeutics GPO=Group Purchasing Organization Other Key Considerations: Formulary

Manufacturer Hospital Considerations Considerations • Medication availability • Packaging & • History shortages & labeling recalls • Product storage & • Handling practices administration • Supply chain security • Interchangeability • Patient assistance programs • Indications • IT support

Griffith N, et al. Hosp Pharm. 2014;49(9)813-825. Biosimilar Task Force

• Members of departments involved with transition from reference product to biosimilar • Map out transition process and launch date • Determine the operational impact (inpatient/outpatient) of biosimilar adoption

Griffith N, et al. Hosp Pharm. 2014;49(9)813-825. Tyler LS et al. Am J Health Syst Pharm 2008;13:1272-1283. Biosimilar Task Force: Operational Impact

• Create biosimilar policy & procedures • Patient consent • EMR implementation • Financial authorization for preferred biosimilar • Process for outpatient denial of biosimilar • Transition decision • Naive patients versus switching patients • Education • Nurses, pharmacists, physicians, patients • Pharmacy inventory & storage

EMR=electronic medical record Griffith N, et al. Hosp Pharm. 2014;49(9)813-825.;Tyler LS et al. Am J Health Syst Pharm. 2008;13:1272-1283. Other Factors

• Be prepared to carry different products • Be prepared to re-evaluate economic evaluation • Policies change • Biosimilar payer restrictions • Monitoring • Determine who will monitor biosimilar integration • Establish metrics • Establish timelines for follow-up Pegfilgrastim Biosimilar Implementation Timeline

Month Preparing for Biosimilar Use Formulary Evaluation and Full Transition

Oct 2018 • Assess scope of impact N/A • Identify affected ordering tools Nov 2018 • Determine availability and • Prepare formulary monograph communicate use to wholesaler Dec 2018 • Convene stakeholders • Identify evidence gaps that may preclude full biosimilar • Update charts and references transition • Configure medication record • Identify patients enrolled in PAP for reference product • Procure product • Determine financial impact Jan 2019 • Payer policy requiring biosimilar • P&T committee review and formulary addition of a goes into effect; product and biosimilar product, TBD based on pricing opportunities medication record available for use • Manage inventory (weekly counts until supply is depleted) • Update consent forms to include nonproprietary names or equivalent

MD Anderson Cancer Center Villanueva M, et al. Am J Health Syst Pharm. 2021;78(3)249-260. Pegfilgrastim Biosimilar Implementation Timeline

Month Preparing for Biosimilar Formulary Evaluation and Full Transition Drug Use Feb 2019 N/A • Explore pricing opportunities and determine formulary product • Configure biosimilar medication orderable record and swap for reference in standard of care treatment protocols Mar 2019 N/A • Set go-live date based on supplies and timeline for treatment protocol updates • Validate biosimilar medication record swaps • Incorporate into workflows for financial clearance and prior authorization Apr 2019 N/A • Communicate formulary change • Formulary transition go-live (newly applied treatment plans) May 2019 N/A • Transition current patients • Formulary deletion of reference product once supply is depleted, protocol amendments are approved, and active treatment plans have been updated

Villanueva M, et al. Am J Health Syst Pharm. 2021;78(3)249-260. MD Anderson Cancer Center Key Considerations: MD Anderson Experience

• Collaboration of pharmacy and pharmacy informatics personnel • Implementing optimal ordering tools • Implications on research protocols (e.g., consenting process) • Protocol amendments • Stocking the reference and biosimilar product(s) during transition period and potentially beyond • Processes to oversee inventory and minimize error risk

Villanueva M, et al. Am J Health Syst Pharm. 2021;78(3)249-260. Summary

• Opportunity for health systems to improve financial health • Key preliminary steps include determining financial impact and provider acceptance • P&T formulary preparation and approval are vital to biosimilar adoption • All impacted stakeholders must convene and map out mechanics to operationalize process • Inpatient and outpatient settings Questions & Answers Thank you!