Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 1
Biosimilars and the Changing Landscapeof Biologic Manufacturing
September 8, 2017
Featured Speaker: Steven Lucio, Pharm.D., BCPSAssociate Vice PresidentClinical Solutions and Pharmacy Program DevelopmentVizientIrving, Texas
LUNCH AND LEARN
CE Activity Information & Accreditation
ProCE, Inc. (Pharmacist and Tech CE)
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Funding: This activity is self‐funded through PharMEDium.
It is the policy of ProCE, Inc. to ensure balance, independence, objectivity and scientific rigor in all of its continuing education activities. Faculty must disclose to participants the existence of any significant financial interest or any other relationship with the manufacturer of any commercial product(s) discussed in an educational presentation. Dr. Lucio has no relevant commercial and/or financial relationships to disclose.
Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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Biosimilars and the Changing Landscape of Biologic
Manufacturing
September 8, 2017
Steven Lucio, PharmD, BCPSAssociate Vice PresidentVizient
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Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
ProCE, Inc.www.ProCE.com 4
Objectives
• Describe the financial imperative for competition within the biologic pharmaceutical market
• Review the nuances of biologic manufacturing and the implications for biosimilar development
• Discuss the principles for biosimilar development and approval
• Evaluate the anticipated economic and clinical practice impact of biosimiars
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Disclosures
• Steven Lucio has nothing to disclose.
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Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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Why Should We Care About Biosimilars?
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2010 2016
Total Spend = $307.4 billion Total Spend = $450 billion
Rank Drug Name Total Sales (billions)
Rank Drug Name Total Sales (billions)
1 Atorvastatin (Lipitor) $7.2 1 Adalimumab (Humira) $13.6
2 Esomeprazole (Nexium) $6.3 2 Ledipasvir/sofosbuvir(Harvoni)
$10.0
3 Clopidogrel (Plavix) $6.1 3 Etanercept (Enbrel) $7.4
4 Salmeterol/Fluticasone (Advair Diskus)
$4.7 4 Insulin glargine (Lantus Solostar)
$5.7
5 Aripiprazole (Abilify) $4.6 5 Infliximab (Remicade) $5.3
6 Quetiapine (Seroquel) $4.4 6 Sitagliptin (Januvia) $4.8
7 Montelukast (Singulair) $4.1 7 Salmeterol/Fluticasone (Advair Diskus)
$4.7
8 Rosuvastatin (Crestor) $3.8 8 Pregabalin (Lyrica) $4.4
9 Pioglitazone (Actos) $3.5 9 Rosuvastatin (Crestor) $4.2
10 Epoetin alfa (Epogen) $3.3 10 Pegfilgrastim (Neulasta) $4.2
IMS, The Use of Medicines in the United States: Review of 2010; QuintilesIMS, Medicines Use and Spending in the U.S., a Review of 2016 and Outlook to 2021Blue = small molecule drugs, red = biologic medications
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Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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Why Are We Talking about Biosimilars? (Total Spending on Medicines –
billions)
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The Consequence of “No” Competition
Nat Biotechnol. 2016;12:1231‐1241.
*WAC = wholesale acquisition cost, a list price paid by distributors to drug companies
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Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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The Basics of Biosimilars
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What is a Biosimilar? A “highly similar” version of a branded biologic approved through an abbreviated, yet extremely rigorous regulatory process. Biosimilars are more complicated than generics
since biologics are more complex than small molecule drugs.
Aspirin
Monoclonal antibody biologic (e.g. adalimumab, bevacizumab, rituximab)
N Engl J Med. 2011;365:385‐388. 14
Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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The Principles of Biologic Manufacturing
• As compared to small molecule drugs, all biologics products, whether originator reference or biosimilar, are:• More structurally complex
• More difficult to manufacture and demonstrate variability in their production
• And are more likely to elicit immunogenic responses
• Pharmacists, pharmacy technicians, and even more so physicians, have a limited awareness of these aspects of pharmaceutical manufacturing
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Biologic Medications Are More Complex Than Small Molecule Drugs
Morphine C17H10NO3
Infliximab C6428H9912N1694O1987S46
FilgrastimC845H1343N233O243S9
©2014 Novation Confidential.16
Ondansetron C18H19N3O
Norepinephrine C8H11NO3
EpoetinC815H1317N233O241S5
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Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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Biologic Manufacturing Is More Complicated
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…And Subject to Variabiliy
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Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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Biologics Can Generate Immune Responses
Product Antibodyformation (%)
Erythropoietin < 1
Factor VIII 15‐52
Factor IX 1‐2
Interferon α 44
Interferon β < 5
IL1 Ra 2
Growth hormone 1‐2
Infliximab 17‐60
• Biologics are large globular proteins that can induce a range of immune responses
• Factors contributing to immunogenicity:• Post‐translational
modifications
• Higher order structure
• Aggregation
Nephrol Dial Transplant. 2006;21[Suppl 5]:v4‐v8, Nat Rev Drug Discov. 2012;11:527‐540, J Investig Allergol Clin Immunol.2008;18:335‐342.
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Understanding Biosimilar Legislation
2020
Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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Biologics Price Competition and Innovation Act of 2009
• Signed into law on March 23, 2010• Created the 351(k) or “biosimilar”
pathway granting FDA authority to approve “highly similar” versions of previously approved reference biologics
• Intended to be an “abbreviated” process
• Biosimilars must not have any clinically meaningful differences in safety, purity and potency as compared to the reference product.
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Approval Pathways (Small Molecules)
Product type Application typeApplication pathway
Clinical studies
Applicationrequirements
Drug(Food Drug and Cosmetic Act)
New Drug Application (NDA)
505(b)1 YesFull evaluation of safety and efficacy
505(b)2 YesStudies do not have to be done by the application sponsor
Abbreviated New Drug Application (ANDA)*
505(j) NoApproval based upon bioequivalence determination
*Created by Hatch‐Waxman AmendmentsAm J Health‐System Pharm. 2013;70:2004‐2017.
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Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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Approval Pathways (Biologics)
Product type Application typeApplication pathway
Clinical studies
Applicationrequirements
Biologic(Public Health Service Act)
Biologics License Application (BLA)
351(a) YesFull evaluation of purity, safety and potency
BiosimilarApplication (established 2010)
351(k) YesYes, but abbreviatedprocess (one clinical trial)
Am J Health‐System Pharm. 2013;70:2004‐2017.
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Totality of the Evidence
Clinical
Animal Studies
Clinical Immunogenicity
Clinical Knowledge (ie, Post-Market Experience)
Human Pharmacokinetics and Pharmacodynamics
Structural and Functional Characterization
The more work you do here…
…the less you should have to do
here.
Adapted from FDA Webinar: Biosimilar Biological Products, available at: http://www.fda.gov/AboutFDA/Transparency/Basics/ucm364686.htm, (accessed 2015 September 26). 24
Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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Biosimilar Analytical Characterization
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/ArthritisAdvisoryCommittee/UCM484859.pdf, (accessed 2017 January 20).
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Novel Aspects about Biosimilars
Naming and Interchangeability
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Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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Biologic Naming Considerations
• Question: What name do you use for a generic drug?
• Answer: The generic name.
• Question: What name do you use for a biosimilar?
• Answer: It’s complicated!
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What’s in a Name?• Two names for biologics
– Core name = (e.g. infliximab)
– Proper name = core name plus four letter suffix (e.g. infliximab‐dyyb)
• Suffix must be unique and devoid of meaning
– Will ultimately apply to all biologics• Why?
– Prevent inadvertent substitution– Improve pharmacovigilance– Encourage use of FDA‐designated suffixes– Advance accurate perceptions about biologicals
http://www.fda.gov/downloads/drugs/guidances/ucm459987.pdf, (accessed 2017 September 4).28
Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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Naming in PracticeCurrent Proposed
Filgrastim Filgrastim‐jcwp
Filgrastim‐sndz Filgrastim‐bflm
Tbo‐filgrastim Filgrastim‐vkzt
Epoetin alfa Epoetin alfa‐cgkn
Infliximab Infliximab‐hjmt
• Approved biosimilars with proper names per guidance: infliximab‐dyyb, etanercept‐szzs, adalimumab‐atto, adalimumab‐abda, infliximab‐abda, adalimumab‐abdm
• No timeline for implementation of proposed proper names for existing products
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM459987.pdf, (accessed 2017 September 4). 29
Interchangeability (Purple is the New Orange)
• It is possible for a biosimilar to be declared as interchangeable, however,
• It is more difficult to obtain this designation,
• Usually not granted on initial approval,
• And the specific requirements are still under development
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM537135.pdf, (accessed 2017 September 3).
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Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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States Interchangeability Designation
• 36 states have considered legislation
– 35 states, plus Puerto Rico have been signed into law
• Common features
– FDA determination as interchangeable – “Purple Book”
– Physician dispense as written authority
– Physician notification, patient notification and consent of substitution
– Record keeping requirements
– Cost information to the patient
http://www.ncsl.org/research/health/state‐laws‐and‐legislation‐related‐to‐biologic‐medications‐and‐substitution‐of‐biosimilars.aspx, (accessed 2017 July 31).
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And Then There Were Six (Approved Biosimilars)
• First biosimilar ‐ Filgrastim‐sndz (Zarxio®; Sandoz)
• Launched September 3, 2015
• Second biosimilar ‐ Infliximab–dyyb (Inflectra®; Celltrion/Pfizer)
• Launched November 2016
• Third biosimilar – etanercept‐szzs (Erelzi™; Sandoz)
• Estimated launch date: ??????
• Fourth biosimilar – adalimumab‐atto (Amjevita™; Amgen)
• Estimated launch date: ??????
• Fifth biosimilar – infliximab‐abda (Renflexis™; Samsung/Merck)
• Launched July 24, 2017
• Sixth biosimilar – adalimumab‐abdm (Cyltezo™; Boehringer Ingelheim)
• Approved August 25, 2017 – estimated launch date????
The Pink Sheet, FDA Performance Tracker, Pending Biosimilars (subscription), (accessed 2017 February 7); Drugs@FDA, (accessed 2017 August 29); http://www.mrknewsroom.com/news‐release/corporate‐news/merck‐announces‐us‐launch‐renflexis‐infliximab‐abda‐biosimilar‐remicade‐ (accessed 2017 August 31).
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Biosimilars and the Changing Landscape of Biologic ManufacturingPharMEDium Lunch and Learn Series
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Biosimilar MissesApplications Requiring More
Information • Filgrastim
• Apotex – likely complete response letter
• Pegfilgrastim
• Apotex – likely complete response letter
• Sandoz – confirmed complete response letter
• Coherus – confirmed complete response letter
• Epoetin
• Pfizer – complete response letter
The Pink Sheet, FDA Performance Tracker, Biosimilars, (accessed 2017 July 31).
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Biosimilar Pipeline for 2017‐2018INN Manufacturer
Application Submitted
Estimated FDA Approval Date
Bevacizumab (ABP 215) Amgen and Allergan 11/2016 9/14/2017
Trastuzumab (MYL‐1401O)
Mylan and Biocon 11/2016 12/3/2017
Pegfilgrastim (MYL‐1401H)
Mylan and Biocon 12/2016 10/2017
Rituximab (CT‐P10) Teva and Celltrion 4/2017 2/2018
Trastuzumab (CT‐P6) Teva and Celltrion 5/2017 03/2018
Trastuzumab (ABP 980) Amgen and Allergan 7/2017 05/2018?
The Pink Sheet, FDA Performance Tracker, Biosimilars, (accessed 2017 July 31); https://www.amgen.com/media/news-releases/2017/07/amgen-and-allergan-submit-biosimilar-biologics-license-application-for-abp-980-to-us-food-and-drug-administration/ (accessed 2017 September 4).
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What Have We Learned from Biosimilars Approved to Date?
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What Savings Have We Seen?
• Filgrastim‐sndz
– 15% initial discount (WAC)
• Tbo‐filgrastim
– 19% discount (WAC)
• Infliximab‐dyyb
– 15% of originator infliximab (WAC)
• Infliximab‐abda
– 35% of originator infliximab (WAC)
http://www.modernhealthcare.com/article/20160323/NEWS/160319919, (2016 September 27); www.drugcodelookup.com, (accessed 2016 September 27); http://www.bigmoleculewatch.com/2017/07/24/samsung‐bioepis‐and‐merck‐co‐launch‐renflexis‐a‐lower‐priced‐competitor‐to‐inflectra/, (accessed 2017 August 31).
WAC = wholesale acquisition cost
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The Dimensions of Payment (Medical and Pharmacy)
Wholesaler
Manufacturer
Hospital (Acute care)/Outpatient/MD
Patient (Beneficiary)
GPO
Health Plan/ Payer
Pharmacy (Retail)
PBM
AMCP Guide to Pharmaceutical Payment Methods, 2013 Update, http://www.amcp.org/pharmaceutical‐payment‐guide/ (accessed 2017 September 3).GPO = group purchasing organization; PBM = pharmacy benefit manager
Flow of Product Flow of Payment
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What Does This Mean to The Healthcare Market?
• Biosimilars have entered the market and more will be added in 2017
• Some uncertainty about these products remain• Relative safety and efficacy
• Approval processes
• Substitution
• While we have seen some savings, the complete extent of discounts remains to be determined.
• Biosimilars are critical to any efforts aimed at slowing the increasing cost of care and also reinforce the importance of high quality manufacturing.
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