This document discusses biosimilar drugs. It begins by explaining that biosimilars are biologic medications that are highly similar to but not exact copies of an original biologic. It then discusses regulatory concerns around biosimilar development and approval including ensuring safety and effectiveness given potential immunogenicity issues. The document provides an overview of some biosimilars currently approved in other countries and areas of concern regarding biosimilar use such as interchangeability, pharmacovigilance, and naming.

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Faculty of Pharmacy
Course Code: MPL104T
Lecture No. 33
Biosimilar

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Faculty of Pharmacy
Content
• Biosimilars
• Regulatory concerns regarding biosimilar development

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Faculty of Pharmacy
Lecture objectives
By the end of this lecture, students will be able to:
• Describe what is biosimilars
• Discuss some regulatory concerns regarding biosimilar
development
• Some biosimilars currently on the market

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Faculty of Pharmacy
Biologics Are Complex
• Biologics are innovative medications that aren’t made, they are grown in
living cells
• Biologics are complex molecules– up to 1,000 times larger than
conventional medicine
• Manufacturing a biologic is a complex process that takes several months
from start to finish
• It’s important to remember that biologic medicines can never be exactly
duplicated by two different manufacturers in the way that simpler
medications can

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Faculty of Pharmacy
Biologics Have Revolutionized Healthcare
• Although relatively new, biologics are already used by more than 350
million patients worldwide
• Biologic medicines revolutionized how diseases and conditions such
as rheumatoid arthritis, Crohn’s disease, hemophilia, multiple
sclerosis, and many other disorders are treated
• Patterned after proteins the body itself produces, biologics can treat
many serious diseases in ways conventional medicines cannot

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Biosimilars
• Biosimilars are products that are “highly similar” to (but not exact copies of)
the reference biologic product
• As a part of the Affordable Care Act (ACA), Congress provided the Food &
Drug Administration (FDA) authority to review and approve biosimilar
versions of FDA approved biologic medicines. The FDA is in the process of
developing guidelines to approve biosimilars
• While there are a small number of biosimilars approved in several other
countries, there are currently none approved for use in the United States
• The FDA received its first application for approval of a biosimilar in July 2014

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Faculty of Pharmacy
What Biosimilars Are…And Are Not
• As the name suggests, biosimilars are similar to a particular biologic,
they are not the same
• All biosimilars differ from the innovative product and from each
other
• They are not generic biologics

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Why There Can Be No “Generic Biologics”
• The active ingredient of a biosimilar can, at best, only resemble that
of the original biologic
• How an innovator company makes its biologic can never be
duplicated down to the last detail; a biosimilar is made using different
cells and different processes

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Ensuring Safety And Effectiveness
• The variations between an innovator biologic and a biosimilar could
potentially trigger an attack against a biosimilar by the body’s
defenses
– This could cause unwanted and/or unsafe symptoms or render the
biosimilar, and possibly the original biologic, less effective
• To ensure comparable safety and effectiveness, biosimilars require
more thorough testing than generic medicines

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Access to Biologics and Patient Welfare
• It is important to provide access to biologic treatments for patients
who need them, and biosimilars play a part in meeting this goal
• An equally and perhaps more important consideration is to ensure
patient safety and welfare in all stages of development, approval, and
monitoring of biologics, including biosimilars

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Important Issues for Patients
As federal agencies and the states implement the new biosimilars law,
they are making important decisions about the regulation of biosimilars
that are crucial to assuring patient safety.
• Interchangeability: This year, the FDA will be decide what standards
must be met for a biosimilar medicine to be judged
“interchangeable” with the original biologic medicine. Strict
standards are needed to ensure patient safety

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Important Issues for Patients
• Rigorous Testing For Each Condition: The FDA will be determining whether drug
companies must conduct rigorous clinical testing to prove that a biosimilar works
safely in each distinct group of patients with that disease. Failure to perform
adequate testing in each group of patients and disease type may put patients at
risk
• Naming: Using a distinguishable but related non-proprietary name for biosimilar
medications (i.e., distinguishable from the original biologic) would enable medical
professionals and the FDA to better track these products and more easily access
any adverse reactions that may occur in patients who use biologics, including
biosimilars

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Important Issues for Patients, (Continued)
As federal agencies and the states implement the new biosimilars law, they are making
important decisions about the regulation of biosimilars that are crucial to assuring
patient safety.
• FDA Transparency: Improved transparency throughout the application and
approval process of biosimilars is important to assure appropriate oversight and to
ensure that all voices, particularly those of patients, are heard.
• Substitution/Notification: Because even an interchangeable biosimilar will not be
identical to the original biologic medicine, most doctor and patient groups feel it is
important for a prescribing doctor to be notified after a pharmacist substitutes a
biosimilar for a prescribed biologic medicine. A biosimilar that is not
interchangeable should only be used if prescribed by an appropriate health
professional.
• Recordkeeping: Ensuring pharmacists maintain records of substitutions for
significant periods of time would allow the medical community to track long-term
treatment outcomes of biosimilars.

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What United Spinal Association Has Said About
Biosimilars
• “The FDA is expected to publish proposed guidance for public comment this year
related to key aspects of implementation of the biosimilars law. We need Congress
to hold oversight hearings on this important process and we urge the FDA to
release guidance as soon as possible that ensure patient safety, patient access to
the right biologic medicines, patient choice and full transparency”
• “Choice should be at the center of any decision to substitute or switch therapies
and should only be decided by the patient and provider. Patient choice needs to be
preserved and regulatory decisions must be based on sound science”
• “Biosimilar regulations must put patient safety first. Policymakers and regulators
must address appropriate patient safety and efficacy concerns as they relate to
decisions around interchangeability, clinical indications, labeling, naming and
substitution”
– Particular attention must be given to assure that rigorous clinical testing proves
that a biosimilar works safely in each and every condition or disease for which
it is approved to be prescribed, as well as in each distinct group of patients with
that disease

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Biosmilars
• Are Biosimilars Generic Versions Of Biologic Medications?
• What Is A Biologic Medication?
• “Any virus, therapeutic serum, toxin, antitoxin, or analogous product
applicable to the prevention, treatment, or cure of diseases or
injuries”
• Hormones (insulin, growth hormone)
• Blood and Blood Products
• Vaccines
• Interleukins
• Antibodies (bevacizumab, trastuzumab)

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What is A Biosimilar?
• A biologic product that is “highly similar” or interchangeable with a biologic
product
• Established in US by the Biologics Price Competition and Innovation Act of
2009
• No clinically meaningful differences in terms of safety, purity and potency
• Available in same dosage strength and form
• Manufactured according to current Good Manufacturing Practice (cGMP)
regulations,
• Synonyms: follow-on biologic, follow-on protein, generic
biopharmaceutical, biogeneric, comparable biologic, subsequent-entry
biologic

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Why Do We Care About Biosimilars?
• Biologic medications:
- Very commonly used
- Very expensive
- Use is rapidly increasing: Nearly 200 biologic and recombinant
biotechnology medicines helping 800 million patients worldwide -
Patents are expiring
• Pharmacists will play a key role in future utilization

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What Biosimilars Are Already On The Market?
• USA: Filgrastim-sdz (Zarxio)
Recently rejected several products
• EU: Insulin Glargine (Abasaglar) - Epoetin alfa (Abseamed, Binocrit,
Epoetin alfa Hexal) - Epoetin Zeta (Retacrit, Silapo) - Etanercept
(Benepali) - Filgrastim (Accofil, Biofrastim, Filgrastim Hexal, Filgrastim
Ratiopharm, Grastofil, Nivestim, Ratiograstim, Tevagrastim,Zarzio) -
Follitropin alfa (Bemfola, Ovaleap) - Infliximab (Inflectra, Remsima) -
Somatotropin (Omnitrope, Valtropin)

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Faculty of Pharmacy
• Biological medicines are medicines that are made by or
derived from a biological source, such as a bacterium, yeast or
blood. They can consist of relatively simple molecules, such as
human insulin or erythropoietin, or complex molecules such
as monoclonal antibodies

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• A biosimilar medicine is a biological medicine that is similar to
another biological medicine which has already been granted
marketing authorisation. The standard approach to licensing of a
generic medicine, where the medicine must demonstrate
bioequivalence (that is the bioavailability of the generic medicine
must not differ significantly when given at the same dosage under
similar conditions), is not sufficient for biosimilar medicines. For
licensing in the European Union, the manufacturer of the biosimilar
medicine must demonstrate that the medicine is:
• similar to the original reference product and does not have any
meaningful differences from the original reference product in terms

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This contains prescribing principles to:
– promote the safe introduction of biosimilar medicines
– promote prescriber confidence
– encourage a consistent approach across NHSScotland
– support National Procurement
– support the review of the Scottish Medicines
Consortium policy on biosimilar medicines, and
– recognise the potential savings that can be achievable
within NHSScotland by the use of biosimilar
medicines.

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Faculty of Pharmacy
• The prescribing framework is presented in the format of a series of
frequently asked questions, with additional supportive detail
• These FAQs are summarised in the next few slides
• For full information please refer to the prescribing framework
document
• Healthcare Improvement Scotland facilitated collaboration between
ADTCs and an expert advisory group to develop the framework.
– A series of meetings were held and consultation with ADTCs
– Advisory group members were drawn from relevant specialist
clinical areas across NHS Scotland

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Q: Should biosimilar medicines be used?
A: Use of biosimilar medicines agrees, they should be considered as a
treatment option for appropriate patients for whom a biological
medicine is being considered as part of their treatment pathway

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Q: Can patients established on a biological medicine be
switched to another biological medicine, for example a
biosimilar?
A: Individual patients may be switched to another biological
medicine, including a biosimilar medicine, as part of a clinician-
led management programme which has appropriate monitoring
in place

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Q: Are different approaches to the use of biosimilar medicines
required in different clinical specialties?
A: There are differing clinical characteristics within specialties
which may be important to consider when using biosimilar
medicines
While practice is evolving, some specialties may consider that
it is most appropriate to use biosimilar medicines in new
patients

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Faculty of Pharmacy
Q: Are there any specific efficacy or safety concerns associated with
the use of biosimilar medicines?
A: There are no specific efficacy or safety concerns identified for
biosimilar medicines but, as for all biological medicines, clinical
experience with biosimilar medicines is still emerging to guide their
use
As for all new medicines, adverse drug reactions to biosimilar
medicines should be reported through the Yellow Card Scheme

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Q: How should biological medicines, including biosimilar
medicines, be monitored?
A: Clinical outcomes for individual patients on any biological
medicine should be measured using established recognised
systems for monitoring disease activity and response to
treatment
Clinical registries are being established for a number of
biological medicines. It would be appropriate to explore the
expansion of these databases to capture details of biosimilar
medicines

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Faculty of Pharmacy
Q: How should biological and biosimilar medicines be
prescribed and product details recorded?
A: Biological medicines, including biosimilar medicines, should
be prescribed by both generic and brand name and the
brand name and batch number should be recorded on the
patient’s prescription, case record or other appropriate
clinical system

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Q: What information should be provided to patients?
A: The manufacturer’s patient information leaflet should be
supplied to all patients receiving any medicine, including a
biosimilar medicine

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Areas of Concern
• Prescriber Confidence
• Interchangability/Substitution
• Immunogenicity
• Pharmacovigilence
• Naming
• Education

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Prescriber Confidence
• As with anything new, much we still do not know
- Provider’s ultimately want to Do No Harm
- What Medication is pt actually receiving?
- If a substitution occurs, when, by whom, to what,
consistently or inconsistently?
- Are they really the same?
- Who is going to have oversight and monitor for issues?

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Interchangability/Substitution
• Do not rush biosimilars, don’t undermine acceptance -
“Dispense As Written” - More data and slow introduction into
clinical practice will allow monitoring
• Above all: GOOD COMMUNICATION between Provider,
Patient, and Pharmacy

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Immunogenicity
• All biologics have potential to contribute to an immune
response
- Various product and patient related factors
- Product: structural, processing, formulation, storage,
handling, presence of impurities
- Patient: genetic background, immune status, route of
administration
• Adverse events unique to biosimilars may be found due to
slight differences - Reactions can take up to several months to
manifest

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Pharmacovigilence
• Potential for immunogenicity when switching between
innovator and biosimilar products
• Data on switching is important
• Post-marketing pharmacovigilience is needed to detect and
assess
• Rare but serious events unlikely to be detected prior to
marketing

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Naming
• Importance of sorting out Naming:
• >30 biosimilars to stimulate red blood cell production
stimulating agents on market in Thailand
• One (or more) caused a deadly condition known as Pure Red
Cell Aplasia (PRCA)
• Since all share the same INN, difficult to determine which
products contributed to this issue

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Education For Pharmacists
• Substituting products at the dispensing level
• Developing P&T policies regarding use
• Understanding cost/coverage
• Input on laws and regulations regarding use
• Educating other healthcare providers
• Educating patients
• Ongoing surveillance/pharmacovigilance

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• What are biosimilar drugs?

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Biologics vs. Small Molecule Drugs
Mellstedt H. EJC Supplements 2013;11:1-11.

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Small Molecule Synthesis: Aspirin

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Manufacturing of Small Molecules
1. Chemical process based on a series of
controlled and predictable chemical
reactions
2. Process is standardized between
manufacturers
3. Final structure easily verified
4. Contaminants are quantifiable

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Biologic Categories
• Monoclonal antibodies
• Complex sugars
• Blood derivatives
• Vaccines
• Recombinant or purified proteins
– Cytokines
– Thrombolytic agents
– Enzymes

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Biosimilar Manufacturing
• Several major steps included in development
– Modifying the selected gene of interest
– Inserting the desired gene into a specific host cell
– Replicating cell line and increased protein
expression
– Harvesting protein products from the cell
– Purifying the selected protein
• More patents on the process than on the drug

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Biosimilar Manufacturing
http://www.pharmqd.com Accessed 2014 Oct 16.

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Similarities and Differences
“Similar” vs. Reference Product
BIOSIMILAR Specification Comparison with REFERENCE
Formulation May be different
Delivery device/container May be different
Routes of administration Licensure depends on application
Conditions of use Licensure includes all indications for
reference product (recent precedent)
Strength Must be the same
Specific potential molecular differences Amino acid substitution
N- and C-terminal modifications
Mismatched disulfide bonds
Post-translation modifications folding
Carboxylation
Formylation
Glycosylation
Methylation
Phosphorylation
PEGylation
http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm259809.htm

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Are biosimilar drug issues new ?
Which, if any, are relevant to current discussion?
• Human Growth Hormone
– First to be substituted
• Human Insulin
– Many choices, little hesitation to interchange
• Interferon Alpha 2a, 2b, Beta, Gamma
– Payer directed formulary equivalence / interchange
• Influenza Vaccine
– Multiple manufacturers; you provide what you can get
• Heparin
– Harvested, purified, equivalence by batch
• Low molecular weight heparin (LMWH)
– Significant dosing issues when interchanged
• Anti-infectives
– Therapeutic Class representative for sensitivity tests
• CMS considered erythropoietin and darbepoetin “Functional Equivalents”

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FDA Approval Pathways
†FDCA = Federal Food Drug and Cosmetic Act
¥PHSA = Public Health Service Act
Drugs
• Small-molecules
• Approved via FDCA
Biologics
• Approved via PHSA¥
New Drug
Application
(NDA)
505(b)(1)
Safety and Efficacy
must be
demonstrated
Abbreviated New
Drug Application
(ANDA)
505(b)(2)
Bioequivalence
must be
demonstrated
Biologics License
Application
(BLA)
351(a)
Safety and Efficacy
must be
demonstrated
Biosimilar Biologics
License Application
351(k)
Must demonstrate
that it is highly similar
to 351(a) reference
Interchangeable
biosimilars require
more data

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Faculty of Pharmacy
Many types of biologic products
Reference or
Originator
Biosimilar Interchangeable
Biosimilar
New biologic
approved via
BLA
Depth of data
submitted to the
FDA
“Standard” data
package
Abbreviated data
package
Abbreviated data
package, more
information on
efficacy and safety
“Standard” data
package; efficacy
and safety on its
own merit
Compared to
reference?
N/A Yes Yes Not Required
Current example
in USA
Filgrastim
Neupogen ®
Filgrastim-sndz
Zarxio ®
Not Yet Tbo-filgrastim
Granix ®

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Faculty of Pharmacy
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

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Biosimilar Pharmacovigilance:
Role of the Pharmacist
• Monitor and report
– Adverse events: FDA MedWatch
– Medication errors
• Correct assessment of safety event
– What was ordered vs. what patient received ?
• Maintenance of EMR
• Bar code administration
• Medication reconciliation for all providers
• Consider transitions of care

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Does coding help differentiate ?
• NDC and HCPCS codes can support differentiation
• Billing claims data can be a useful in pharmacovigilance
– Outcomes
– Adverse Events
• Problems with using billing data
– NDA: Leuprolide Acetate (depot formulations)
• Lupron Depot: intramuscular injection
• Eligard: subcutaneous injection
• 2013 HCPCS code:
• J1950: Injection, leuprolide acetate (for depot suspension), per 3.75 mg
– BLA: Epoetin alfa
• Procrit® and Epogen®
• 2013 HCPCS codes:
• J0885: Injection, epoetin alfa, (for non-ESRD use), 1000 units
• J0886: Injection, epoetin alfa, 1000 units (for ESRD on dialysis)

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Biosimilar Pharmacovigilance
Zuñiga L, Calvo B. Pharmacoepidemiol Drug Saf. 2010 Jul;19:661-9.
Felix T, et al. Nat Biotechnol. 2014 ;32:128-30.
Casadevall N, et al. Expert Opin Biol Ther. 2013;13:1039-47.
Pharmacovigilance
• Define monitoring parameters
• Easy reporting methods
• Real-time data
• Ensure traceability
Risk minimization
• Healthcare provider feedback and
communication
• Recalls and alerts
• REMS?
Constant Monitoring to Identify and Characterize Safety
Risk
• Naming standards
• Integration into electronic medical
record (EMR)
• Drug codes: HCPCS, NDC, etc.
• Prospective registries

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AGENDA
• What are biosimilar drugs?
• Regulatory issues
• Safety concerns and Pharmacovigilence
• Indications for use
• Financial implications
• Summary / Key Points

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Interchangeability Definition
• Interchangeability definition
– “Biosimilar to the U.S.-licensed reference biological product …
expected to produce the same clinical result as the reference
product in any given patient.”
– “For a biological 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 biological product and
the reference product will not be greater than the risk of using the
reference product without such alternation or switch”
PHS Act, section 351(k)(4). http://www.fda.gov/downloads/drugs/
guidancecomplianceregulatoryinformation/ucm216146.pdf. Accessed 2014 Nov 13.

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• Biological products approved by FDA and dates of
approval
• Approval pathway: e.g., 351(a), 351(k)
• Lists if a biosimilar is interchangeable
• Defines exclusivity period
FDA “Purple Book”
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalAppl
ications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm. Accessed 2014 Oct 16.

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“Documented” Practice Standards
Decision Domains Supporting Use
Restricted Formularies
and Clinical Pathways
Evidence
Rated
Compendia
Reference
biologic
labeled
indication
Biosimilar
labeled
indications

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Are Indications Interchangeable ?
• Provider Formulary and P&T committee
– Is the “risk” of unknown worth the “benefit”
– Ability to monitor and report (pharmacovigilance)
– Multiple providers (especially oral chemo)
– What evidence will they require to support interchange
• Payers
– How will payers make their coverage determinations?
– Compendia therapeutic class representatives

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Generics vs Biosimilars

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Summary
• Biologics are innovative medications that aren’t made, they are
grown in living cells
• Biosimilar is a biologic product that is “highly similar” or
interchangeable with a biologic product
• All biologics have potential to contribute to an immune response
• Potential for immunogenicity when switching between innovator
and biosimilar products