Biosimilar Drugs: Overview and Regulatory Issues

1. Phil Johnson MS RPh FHOPA FASHP
Moffitt Cancer Center, Director of Pharmacy (Retired)
Premier Inc., Oncology Director (Retired)
Biosimilar Drugs: Overview
and Regulatory Issues
F L A S C O
November 5, 2016

2. Disclosures
• I have no financial disclosures
relevant to this program.

3. Learning Objectives
• Define Biosimilar Drugs
• Describe the FDA approval process for biologics
• Explain the regulatory issues related to biosimilar
production and use
• Assess the factors relevant to the interchangeability of
biosimilars
• Discuss the financial impact of biosimilar drugs

4. FDA Definitions
• Reference or Originator Biologic
– Approved under FDA 351(a)
• Biosimilar
– Approved under FDA 351 (k)
– Highly similar to the reference product
– No clinically meaningful differences in terms
of the safety profile, purity, and potency
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm. Accessed June 2015

5. • Chemical synthesis vs Grown and harvested
• Homogenous vs Heterogenous output
• Verification of structure (3-D issues for biologics)
• Purification process
• Toxicity
• Protein related issues
• FDA approval
• Cost
Small Molecule vs Biologic Drugs
Mellstedt H. EJC Supplements 2013;11:1-11.
Rak Tkaczuk KH. Semin Oncol. 2014; 41(suppl 3):S3-S12.

6. Biologic / Biosimilar Manufacturing
More patents on the process than on the drug !
http://www.pharmqd.com Accessed 2014 Oct 16.

7. FDA: Demonstrating Biosimilarity
• The clinical efficacy and safety of the “reference” biologic
molecule has already been demonstrated (ie, by the
innovator)
• The biosimilar sponsor only requires evidence that the
candidate biosimilar is not significantly different from the
reference product
– Goal is not to replicate unnecessary clinical trials
– Smaller-scale direct comparisons and extrapolation
• When a biosimilar is approved, there should not be an
expectation that there will be differences in safety and
efficacy
• Example: Infliximab data requirement
– 800 patients with rheumatoid arthritis and ankylosing spondylitis
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/ucm290967.htm. Accessed June 2015.
“Celltrion’s infliximab copy shows path to biosimilars in US”, Nabure Biotechnology, v34, n5, p454,
May 2016

8. FDA “Totality of Evidence”
Comparative Analytical Data
Structural Analyses
• Primary structures / amino
acid sequence
• Higher order structures
(including aggregation)
• Enzymatic post-translational
modifications (eg.
glycosylation,
phosphorylation)
• Active part of molecule is
the same
• Unique requirements for the
specific molecule
Functional Assay
• In vitro
– Biological assays
– Binding assays
– Enzyme kinetics
• In vivo
– Animal models of disease
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/ucm073476.pdf

9. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Dru
gs/AdvisoryCommitteeforPharmaceuticalScienceandClinicalPharmacology/UCM3157

10. FDA Approval Pathways
FDCA = Federal Food Drug and Cosmetic Act
PHSA = Public Health Service Act
HWA = Hatch Waxman Act, 1984
Drugs
• Small-molecules
• Approved via FDCA
Biologics
• Approved via PHSA
New Drug
Application
(NDA)
505(b)(1)
Safety and
Efficacy must be
demonstrated
Abbreviated NDA
(ANDA)
• Approved via
HWA
505(b)(2)
Bioequivalence
must be
demonstrated
Biologics License
Application
(BLA)
351(a)
Safety and
Efficacy must be
demonstrated
Biosimilar License
Application
(ABLA)
351(k)
Must demonstrate
high similarity to
351(a) reference
“Interchangeable
designation requires
more data”

11. Four categories of biologic products
Reference or
Originator
351(a)
Biosimilar
351(k)
Interchangeable
Biosimilar
351(k)
New biologic
approved via
351(a)
Depth of data
submitted to
the FDA
“Standard” data
package
Abbreviated
data package
Abbreviated
data pack; more
information on
efficacy and
safety
“Standard” data
package;
efficacy and
safety on its
own merit
Compared to
reference?
Sets Standard Yes Yes Not Required
Current
examples in
USA
Filgrastim
Neupogen ®
Etanercept
Enbrel ®
Infliximab
Remicade ®
Filgrastim-sndz
Zarxio ®
Etanercept-szzs
Erelzi ®
Infliximab-dyyb
Inflectra ®
Not Yet
Designated;
Indications
same as
reference for
first 3
Tbo-filgrastim
Granix ®

12. Guideline on Similar Biological Medicinal Products (Oct 05)
Guideline on Similar Biological Medicinal Products
Containing Biotechnology-Derived Proteins as Active
Substance: Quality Issues (June 06)
Overarching
Quality
Annexes Epoetin
July 2006
G-CSF
June 2006
Insulin
June 2006
HGH
June 2006
General
Applicable
to all
Biosimilars
Specific:
Product data
requirements
Guideline on Similar Biological Medicinal Products
Containing Biotechnology-Derived Proteins as Active
Substance: Nonclinical & Clinical Issues (June 06)
Nonclinical
& Clinical
Heparin LMWH &
Others Draft
13 biosimilar marketing authorizations have been granted
EMA Model: Biosimilars Regulations
www.ema.europa.eu
EMA=European Medicines Agency

13. Source of Names and Numbers
• Originator Manufacturer
– Reference Product (Trade Name)
• United States Adopted Names (USAN)
– The generic name (Reference Name)
– Provided by AMA
– Generally adopted by FDA
• United States Pharmacopeia (USP)
– Monographs and consistency concerns
• Institute for Safe Medication Practices (ISMP)
– Consults on Naming Clarity and Safety concerns
– Advocates for Labeling standards
• Food and Drug Administration (FDA)
– Ultimately approves product name
– Assigns National Drug Code (NDC)
• Centers for Medicare & Medicaid Services (CMS)
– Assigns HCPCS codes
– Codes usually the same between biosimilars & originator
HCPCS=Healthcare Common Procedure Coding System
Reference
Slide

14. Importance of a Naming Strategy
• Goal:
– Identify relationship between the “biosimilar”
and “reference” / “originator”
• Therapeutic category
• Dosing
– Differentiate products
• Support pharmacovigilance (PV)
• Intended product administered to patient
• Outcomes and ADEs attributed to correct product
• Avoid “sound alike” and “look alike” errors
– Facilitate effective product “track and trace”
(anti-counterfeiting)

15. Naming Options
• Options
– Totally different names from originator
• Preferred by most originator pharmaceutical companies
– Same USAN name as originator
• EU policy
– Unique suffix attached to originator’s USAN
• Error prone because some computer fields truncate long
names
• Facilitates listing adjacent to reference in formulary data bases
• Supported by WHO, ISMP, HOPA
– Unique prefix attached to originator’s USAN
• Precedent with tbo-filgrastim
– Current FDA position
• Open comment period on using meaningful suffix
• Current precedent for 2 Sandoz products:
– Filgrastim-sndz Zarxio ®
– Etanercept-szzs Erelzi ®

16. State Biosimilar Legislation Status
as of October 2014
http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-
medications-and-substitution-of-biosimilars.aspx

17. State Proposals Are Driven By BPCI Act
• Allows approval by FDA of a biosimilar product as
“interchangeable”
– FDA continues work on implementing BPCI Act
– Meanwhile, extrapolates all reference drug indications to the
biosimilar
• States have considered proposals to restrict substitution of
biologic drugs that have not been designated by FDA as
interchangeable
• Supporters of state proposals believe the ultimate decision
on substitution should be left to the patient’s prescribing
physician
– Perhaps concern for patient safety
– Perhaps desire to protect use of “originator” drug
• Opponents believe state proposals are restrictive and
inconsistent with forthcoming national standards
U.S. Senate. Biologics Price Competition and Innovation Act. URL in reference list
U.S. Congress. Sections 7001-7003 (Biologics Price Competition and Innovation Act of 2009) of the Patient
Protection and Affordable Care Act (Public Law 111-148). URL in reference list

18. Frequent Features of State Legislation
http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-and-substitution-of-biosimilars.aspx
• Any biological product under consideration for substitution must be
certified and listed as approved for substitution by the FDA
• No products have gained such approval as biosimilars in the United States
• Prescriber would be able to prevent substitution by stating
“dispense as written” or “brand medically necessary”
• Prescriber must be notified of any allowable substitution made
at a pharmacy
• Individual patient must be notified that a substitute or switch
has been made; in some cases, state law requires patient consent
before any such switch is made
• Pharmacist and the physician must retain records of substituted
biologic medications
• State must maintain a public list of permissible
interchangeable products

19. Enacted State Legislation
• Florida, HB 365 (2013), Chapter 2013-102
http://www.flsenate.gov/Session/Bill/2013/0365/BillText/er/PDF
• North Dakota, SB 2190 (2013)
http://www.legis.nd.gov/assembly/63-2013/documents/13-0511-
04000.pdf?20131023091537
• Oregon, SB 460 (2013), Chapter 342, 2013 Laws,
https://olis.leg.state.or.us/LIZ/2013R1/Measures/Text/SB0460/Enr
olled (contains sunset clause)
• Utah, SB 78 (2013),
http://le.utah.gov/~2013/bills/sbillenr/sb0078.pdf (contains sunset
clause)
• Virginia, SB 1285, (2013), Chapter 544 (contains sunset clause),
http://lis.virginia.gov/cgi-bin/legp604.exe?131+ful+CHAP0544
Reference
Slide

20. Amendment Enacted by State of Florida
(Key Points)
• Section 1. Subsection (6) of section 465.019, Florida 18 Statutes, is
AMENDED to read:
• (6) In a Class II institutional pharmacy, an institutional formulary system
may be adopted with approval of the medical staff for the purpose of
identifying those medicinal drugs, and proprietary preparations, biologics,
biosimilars, and biosimilar interchangeables that may be dispensed by the
pharmacists employed in such institution. …shall establish policies and
procedures for the development of the system in accordance with the joint
standards of the American Hospital Association and American Society of
Hospital Pharmacists for the utilization of a hospital formulary system…..
• Section 2. Section 465.0252, Florida Statutes, is created to read:
• 465.0252 Substitution of interchangeable biosimilar products.
• (3) A pharmacist who practices in a class II or modified 54 class II institutional
pharmacy shall comply with the notification provisions of paragraph (2)(c)
by entering the substitution in the institution's written medical record
system or electronic medical record system.
http://www.flsenate.gov/Session/Bill/2013/0365/BillText/er/PDF

21. FDA: Interchangeability
• The biological product is biosimilar to the reference
product
• It can be expected to produce the same clinical result as
the reference product in any given patient
• For a product that is administered more than once to an
individual, the risk in terms of safety or diminished efficacy
of alternating or switching between use of the product and
its reference product is not greater than the risk of using
the reference product without such alteration or switch
• A product with an interchangeable designation may be
substituted for the reference product without the
intervention of the health care provider who prescribed the
reference product
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm290967.htm
http://www.ncsl.org/research/health/state-laws-and-legislation-related-to-biologic-medications-
and-substitution-of-biosimilars.aspx.

22. • Characterization of Biological products approved by FDA
• Dates of approval and exclusivity period
• Approval pathway: e.g., 351(a), 351(k)
• “Biosimilar and interchangeable products will be listed
under the reference product to which biosimilarity or
interchangeability was demonstrated.”
FDA “Purple Book”
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/Appro
valApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm. Accessed 2014 Oct 16.

23. Documented Practice Standards
Real World Decision Domains
Supporting Use
Restricted Formularies
and Clinical Pathways Evidence
Rated
Compendia
Reference
biologic
labeled
indication
Biosimilar
labeled
indications

24. U.S. Healthcare cost increases are not sustainable !
• 13.8 to 18.1 million cancer patients
– 45% increase in new cases annually
• $104 billion to $173 billion annual cost of cancer drugs
– Associated drug therapy costs rise 27%
– More than 600 drugs in oncology related pipeline, mostly biologics
• 20% to 65% Site of Care from MD Offices to Hospitals
• Therapy choice determined / paid differently
– From Protocols to Pathways to Genomic / Proteomic Testing
– From Fee For Service to Episodic Bundles to Population Health
• Many cancers have become a chronic disease
– 35% increase in number of survivors (18 million by 2022)
– Estimated cost of survivor year = $16,000
“The state of cancer care in America, 2010 - 2020”; ASCO, JOP 3-10-14

25. CMS Billing Guidance, April 2015
• CMS Payment
– Utilize same HCPCS code as Reference Drug
– Initial: 106% AWP
– Then: Biosimilar ASP + 6% Reference ASP
– Reference Product: ASP + 2.3% (varies)
• CMS release:
– “…unique opportunity to achieve measurable cost savings
and greater beneficiary access to expensive therapeutic
treatments for chronic conditions.”
– “CMS is considering policy options for coding of additional
biosimilars and will release further guidance in the future”
– Expects price to be 15 – 30% lower than reference product
http://mobile.biopharma-reporter.com/Markets-Regulations/US-CMS-releases-new-info-around-biosimilar-pricing-
uptake?utm_source=copyright&utm_medium=OnSite&utm_campaign=copyright#.VSPTi_nF-Gl

26. Patient / Co-Pay Assistance ?
• Most originator drugs have PAP
• Most “biosimilar drugs” are produced by
companies that have PAP programs
• To be competitive, providers should insist
on at least the same level of support as
with the originator drug.

27. 7-5-2016 US Federal Court (Amgen vs Apotex) requires
biosimilar manufacturer to give notice to reference manufacturer
and wait 180 days before bringing the drug to market.
Drug (examples) Patent Expires
Lovenox 2012
Neupogen 2013
Epogen 2013
Lantus 2014
Interferon beta 1-a 2015
Neulasta 2015
Synagis 2015
Humira 2016
Rituximab 2016
Erbitux 2016
Remicade 2018
Avastin 2019
Herceptin 2019
Aranesp 2024
Etanercept (Enbrel) approved 9-2016, delayed market release to 3-2017
www.biopharminternational.com/federal-court-weighs-biosimilar-patent-dance
PATENT “CLIFF”
Reference
Slide

28. Impact on
Price
Response
From
Originators
Result
 Prior to biosimilar entry,
originators had already
introduced price discounts
 Biosimilar EPOs are priced at ~
20% less than the originator
brands
 Originators responded to limit
biosimilar uptake
 Questions on the quality, safety,
and efficacy of biosimilars
 Advising clinicians against
switching EPO products
 Questioning the adequacy of EU
pharmacovigilance systems to
effectively monitor biosimilars in
clinical practice
 Clinicians comfortable with the
introduction of biosimilars
 No unexpected safety concerns
identified in 24 months
 Extensive “Post Authorization
Safety Studies” have been
undertaken by the biosimilar
manufacturers to monitor safety
of their products in the market
European EPO Commercial Experience
 Branded EPOs are switched to
biosmiliars on tenders today
(interchangeability)
 Only two biosimilars withdrawn
from market, neither for safety
or efficacy reasons
 EU payors are driving biosimilar
uptake if funding mechanisms
give them influence

29. Summary
• Biosimilar drugs have been used safely and successfully in
Europe for more than 10 years while documenting more
than 20% reduction in cost
– CMS expects 15 – 30% cost reduction
• US now has 3 biosimilar drugs, and one 351(a) approved
competitor product
• FDA has not yet given interchangeability status to a specific
drug, however:
– FDA has extrapolated the reference indications to the
biosimilar
– CMS utilizes the same HCPCS code
– FDA lists biosimilar as a product under the “reference drug” in
the Purple Book
– FDA has not defined naming standard but has utilized
“meaningful 4 digit prefix + reference generic”
• Many payers have directed product substitution (aka
interchangeability) in their formulary
• Significant potential cost savings for patient, provider, and
payer

30. Resources
• HOPA Biosimilar Issue Brief
– http://www.hoparx.org/Health-Policy/default/hp-agenda.html
• ASHP Whitepaper: Biosimilars: Policy, Clinical and
Regulatory Considerations
– http://www.ashp.org/menu/PracticePolicy/ResourceCenters/E
merging-Sciences/Biosimilars.aspx
• NCCN Biosimilars White Paper: Regulatory, Scientific, and
Patient Safety Perspectives
– http://www.jnccn.org/content/9/Suppl_4/S-1.full.pdf+html
• ASCO: Policies, Positions and Guidance
– https://www.asco.org/advocacy-policy/policies-positions-
guidance
• FDA Information on Biosimilars
– http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowD
rugsareDevelopedandApproved/ApprovalApplications/Therape
uticBiologicApplications/Biosimilars/default.htm
Reference
Slide

31. Questions ?