Biosimilars 101: How similar are they? Matthew Marston, Pharm.D., - PDF document

3/20/2018 Biosimilars 101: How “similar” are they? Matthew Marston, Pharm.D., BCPS, BCOP Senior Manager of Clinical Pharmacy Services Miller Drug, LLC Outline • Describe the approval and manufacturing process of biologics • Identify differences between generics and biosimilars • Describe financial and operational implications for oncology practices 1

3/20/2018 Review of Biologics Hospira. http://www.hospira.co.uk/en/about_hospira/biologics/biosimilars_generic_drugs. Accessed 4/1/2016. Small Molecules Biologics • Examples: • Examples: • Filgrastim • Aspirin • Rituximab • Warfarin • Cetuximab • Gabapentin • Made from a variety of • Made through chemical natural sources reactions • Human, animal, or • Easily reproduced • Identical active microorganism • Complex (proprietary) ingredient manufacturing process • Variability is unavoidable 2

3/20/2018 Biologic Manufacturing D’Haens, GR, et al. Journal of Crohn’s and Colitis (2014) 8, 726‐34. Natural Protein Variation • Significant variations in potency exist between lots • FDA requires notification of any change in manufacturing • Variations are not thought to produce clinically meaningful differences 3

3/20/2018 Immunogenicity “The ability of a particular substance, such as an antigen or epitope, to provoke an immune response in the body of a human or animal.” Kahn FA. CRC Press, 2011; 518. http://bcn2012.europeanbioanalysisforum.eu/slides/day%202/ii%20biosimilars/4_sauerborn.pdf 4

3/20/2018 Cost of Biologics • Rising cost negatively impacts patient access • European study demonstrated a direct relationship between GDP and biologic use • Biosimilar competition in US expected to produce $250 billion in cost savings from 2014 to 2024 1. Péntek M, et al. Eur J Health Econ 2014; 15(suppl 1):S35‐43. 2. Express Scripts. http://lab.express‐scripts.com/lab/insights/industry‐updates/the‐$250‐billion‐potential‐of‐ biosimilars. Accessed 4/1/2016 http://www.sandoz‐biosimilars.com/en/biosimilars/why‐biologics‐matter‐en.shtml 5

3/20/2018 Ventola , C. P&T . 2013; 38(5):270‐87. What is a Biosimilar? “A biosimilar product is a biological product that is approved based on a showing that it is highly similar to an FDA‐approved biological product, known as a reference product, and has no clinically meaningful differences in terms of safety and effectiveness from the reference product.” FDA.http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/A pprovalApplications/TherapeuticBiologicApplications/Biosimilars/. Accessed 4/1/2016. 6

3/20/2018 Biosimilars in the U.S. • Biologics Price Competition and Innovation Act of 2009 (BPCI Act) • Part of the Affordable Care Act • Signed into law on March 23, 2010 • 1 st biosimilar filgrastim-sndz (Zarxio) approved in US on March 6, 2015 FDA Approval Process Christl, L. FDA. FDA.gov. Accessed April 7, 2016. 7

3/20/2018 STRUCTURE McCamish M, Woollett G. Clin Pharm & Ther. 2012; 91(3); 405‐17 FUNCTION McCamish M, Woollett G. Clin Pharm & Ther. 2012; 91(3); 405‐17 8

3/20/2018 PK & PD McCamish M, Woollett G. Clin Pharm & Ther. 2012; 91(3); 405‐17 EFFICACY & SAFETY McCamish M, Woollett G. Clin Pharm & Ther. 2012; 91(3); 405‐17 9

3/20/2018 Quintiles. http://www.quintiles.com/microsites/biosimilars‐knowledge‐connect/regulatory‐requirements. Accessed 4/1/2016. Reference Biosimilar’s Manufacturer Biosimilar Manufacturer Product Availability on the (Trade Name) U.S. Market Adalimumab Abbvie Adalimumab‐adbm Boehringer Unavailable (Humira) (Cyltezo) Ingelheim Adalimumab‐atto Amgen Unavailable (delayed (Amjevita) until 2023) Bevacizumab Genentech Bevacizumab‐awwb Genentech Unavailable (Avastin) (Mvasi) Etanercept Amgen Etanercept‐szzs (Erelzi) Sandoz Unavailable (Enbrel) Filgrastim Amgen Filgrastim‐sndz (Zarxio) Sandoz Available (Neupogen) Infliximab Janssen Infliximab‐abda Merck Available (Remicade) (Renflexis) Infliximab‐dyyb Pfizer Available (Inflectra) Infliximab‐qbtx (Ixifi) Pfizer Unavailable Trastuzumab Genentech Trastuzumab‐dkst Mylan / Biocon Unavailable (Herceptin) /Roche (Ogivri) 10

3/20/2018 Other Biosimilar Concepts “Extrapolation” • The FDA may extrapolate approval to indications other than what was studied • “Sufficient scientific justification” required for each indication • Example: Infliximab • Studied in rheumatoid arthritis and ankylosing spondylitis • FDA recently approved biosimilar Inflectra across all infliximab indications Other Biosimilar Concepts “Interchangeability” • Requires additional crossover design trials • Allows pharmacists to interchange without physician approval • Trials conducted in Europe indicate interchanging therapies results in no added risk of immunogenicity 11

3/20/2018 2015 ASCO Policy Brief • Should demonstrate efficacy and safety, including lack of immunogenicity. • Establish a transparent regulatory pathway for approval of biosimilars. • Physician choice between biologic products should not be restricted. • Biosimilars should be subject to careful post-market safety surveillance. • Interchangeability should be established by clinical trials. • Congress should ensure adequate FDA funding to meet new demands. Lyman, GH. ASCO. 2017. https://am.asco.org/biosimilars‐changing‐cancer‐care‐landscape. Challenges to Biosimilars • 2017 Pfizer vs. J&J – infliximab biosimilar • First litigation on biosimilars • Alleged anticompetitive contracts • Possibly linked to slow biosimilar market development • High development cost • Generic drug $1-5 million vs. biosimilar ~$250 million • Lack of understanding in U.S. market 12

3/20/2018 Payment Pitfalls • Reference product dispensed when biosimilar is preferred • Biosimilar dispensed when reference product is preferred • Biosimilar or reference product dispensed prior to obtaining authorization • Authorization for one product obtained and the other is dispensed Medication Safety • Naming convention: • Generic name plus manufacturer suffix • E.g. filgrastim-sndz • Many sites choosing to utilize brand names • Limiting number of formulary products • Inpatient vs. Outpatient • Medication reconciliation • Need for pharmacovigilance 13

3/20/2018 On The Horizon • Treatment vs. Supportive Care vs. Palliative • Problem with extrapolation? • Ex. Trastuzumab, bevacizumab, cetuximab • Plant–Made Biologics (PMBs) • Low production cost • Low risk of pathogen contamination • Ex. Zmapp, Elelyso Chen Q. F1000Res. 2016; 5: F1000 Faculty Rev‐912. Conclusions • Biosimilars offer an opportunity to lower the cost of biologic therapies • Biosimilars are more complex than generics • Significant barriers to market entry currently exist • Careful consideration must be made prior to administering therapy to avoid losses in reimbursement 14

3/20/2018 Biosimilars 101: How “similar” are they? Matthew Marston, Pharm.D., BCPS, BCOP Senior Manager of Clinical Pharmacy Services Miller Drug, LLC • Chen Q. The potential of plants as a system for the development and production of human biologics. F1000Res. 2016; 5: F1000 Faculty Rev‐912. • Christl L. FDA. FDA’s Overview of the Regulatory Guidance for the Development and Approval of Biosimilar Products in the US. FDA. FDA.gov. Accessed April 7, 2016. • D’Haens GR, et al. Future directions in inflammatory bowel disease management. Journal of Crohn’s and Colitis (2014) 8, 726‐34. • Dörner T, et al. The hanging landscape of biosimilars in rheumatology. Ann Rheum Dis 2016;0:1‐9. • Express Scripts. The $250 billion potential of biosimilars. http://lab.express‐ scripts.com/lab/insights/industry‐updates/the‐$250‐billion‐potential‐of‐biosimilars. Accessed 4/1/2016. • FDA. Information on biosimilars. http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApprov ed/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/. Accessed 4/1/2016. • Hospira. Biosimilars Compared to Generic Drugs. http://www.hospira.co.uk/en/about_hospira/biologics/biosimilars_generic_drugs. Accessed 4/1/2016. 15

3/20/2018 • Kahn FA. Biotechnology Fundamentals. CRC Press, 2011; 518. • Lai Z, La Noce A. Key design considerations on comparative clinical efficacy studies for biosimilars: adalimumab as an example. RMD Open. 2016; 2(1): e000154. • Lyman, GH. Biosimilars in the Changing Cancer Care Landscape . ASCO. 2017. https://am.asco.org/biosimilars‐changing‐cancer‐care‐landscape. • McCamish M, Woollett G. The State of the Art in the Development of Biosimilars. Clin Pharm & Ther. 2012; 91(3); 405‐17. • Péntek M, et al. Patients’ access to biological therapy in chronic inflammatory conditions; per capita GDP does not explain the intercountry differences. Eur J Health Econ 2014; 15(suppl 1):S35‐43. • Sandoz. http://www.sandoz‐biosimilars.com/en/biosimilars/why‐biologics‐matter‐en.shtml. Accessed 4/1/2016. • Schiestl M, et al. Acceptable changes in quality attributes of glycosylated biopharmaceuticals. Nature Biotechnology (2011) 29, 310‐12. • Ventola C. Biosimilars Part 1: Proposed Regulatory Criteria for FDA Approval. P&T . 2013; 38(5):270‐87. 16