Program objectives

1. Review complexities of biologics and differences from chemical

drugs

Biosimilars—Scientific and 2. Introduce the US biosimilar regulatory framework

Regulatory Considerations
3. Learn about biosimilar development including design, analytical
studies, and clinical studies

Gustavo Grampp
4. Discuss post-approval considerations including
Regulatory Policy Director, Amgen pharmacovigilance, interchangeability, and substitution
Presented at Maryland Pharmacists Association meeting January 31, 2016

Grampp, Biosimilars—Scientific and Regulatory Considerations. 2

MPhA Meeting January 31, 2016

What is a biologic?
• Biologics are large protein-based therapeutics
– Biologics can include antibodies, recombinant proteins, or
fusion proteins

INTRODUCTION TO
BIOLOGICS
Monoclonal antibody
Neiderwieser D et al. Eur J Haematol 2011;86:277-288.

3 Grampp, Biosimilars—Scientific and Regulatory Considerations. 4

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Amgen Corporate Template 1

 What is a biologic? What is a biologic?
• Biologics are more complex in structure and function • Biologics are more complex in structure and function
than chemical drugs than chemical drugs

Up to 1000×
larger1,2

Complex,
with post-translational
modifications1

Simple,2
well-defined3

Monoclonal antibody1 Acetylsalicylic acid2

~150 kDa ~0.18 kDa Monoclonal antibody Acetylsalicylic acid

1. Roger SD. Nephrology 2006;11:341-346. 2. Prugnaud JL. Br J Clin Pharmacol 2007;65:619-620. 3. Genazzani AA et al. Biodrugs 2007;21:351-356.
1. Lipman NS et al. ILAR J. 2005;46:258-268. 2. Aspirin prescribing information. Available at:
http://www.fda.gov/ohrms/dockets/ac/03/briefing/4012B1_03_Appd%201-Professional%20Labeling.pdf. Accessed September 2015.

Grampp, Biosimilars—Scientific and Regulatory Considerations. 5 Grampp, Biosimilars—Scientific and Regulatory Considerations. 6
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Biologics are made by living cells

through well-controlled processes So what is a biosimilar?
A typical biotechnology manufacturing process includes multiple stages • According to the US FDA, a biosimilar is a biological
product that is highly similar to the reference product
Transfection of
• There are no clinically meaningful differences in terms
Patient
DNA into host cell1 treatment2

of:
Cell line
selection and Refrigeration,2 – Safety
development1 storage,2 and
transport1 – Purity
– Potency
Manufacturer establishes a
unique master cell bank1 Formulation,1 fill,2
and finish2
In other words:

Differences between biosimilars and reference biologics

Cell culture Characterization
and expansion1 and stability2 are expected, but must not be clinically meaningful
FDA, Food and Drug Administration.
Isolation2 and purification1 US Food and Drug Administration. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128.pdf. Accessed
September 2015.
1. Kresse GB. Eur J Pharm Biopharm. 2009;72:479-486. 2. Sharma BG. EJHP Practice. 2007;13:54-56.
Grampp, Biosimilars—Scientific and Regulatory Considerations. 7 Grampp, Biosimilars—Scientific and Regulatory Considerations. 8
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Amgen Corporate Template 2

 Each biosimilar is unique because of Biosimilars are fundamentally different
differences in manufacturing from generics
Biosimilars Generics Biosimilars Generics
Monoclonal Acetylsalicylic acid1 Monoclonal Acetylsalicylic acid1
Known DNA sequence Unique manufacturing Unique biosimilar antibody antibody
SIZE STRUCTURE
Complex with many
Large2 Small2 options for post- Simple5 and
MW = ~150,000 Da3 MW = 180 Da1 translational well defined2
modification4

MANUFACTURING CHARACTERIZATIONS
Each manufactured in a Predictable chemical Difficult to
unique living cell line2 process characterize fully Easy to fully
Similar but not identical Identical copy can be owing to a mixture of characterize6
copy can be made2 made2 related molecules6

STABILITY IMMUNOGENICITY

Sensitive to storage
and handling Relatively stable2 Higher potential2 Lower potential2
conditions2

MW, molecular weight.

1. Aspirin comprehensive prescribing information. Available at: www.fda.gov/ohrms/dockets/ac/03/briefing/4012B1_03_Appd%201Professional%20Labeling.pdf.
1. Roger SD. Nephrology (Carlton) 2006;11:341-346. 2. Mellstedt H et al. Ann Oncol 2008;19:411-419. Accessed January 2013. 2. Genazzani AA et al. Biodrugs 2007;21:351-356. 3. Lipman NS et al. ILAR J 2005;46:258-268. 4. Roger SD. Nephrology 2006;11:341-346.
5. Prugnaud JL. Br J Clin Pharmacol 2007;65:619-620. 6. Gottlieb S. Am J Health Syst Pharm 2008;65(Suppl 6):S2-S8.

Grampp, Biosimilars—Scientific and Regulatory Considerations. 9 Grampp, Biosimilars—Scientific and Regulatory Considerations. 10
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Summary

Biologics are large, complex medicines

developed in living systems

Biosimilars are highly similar, but not

identical to the innovator biologic

Biosimilars differ from generics in REGULATORY FRAMEWORKS

complexity, manufacturing and sensitivity

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Amgen Corporate Template 3

 The US biosimilars pathway was signed In contrast to the regulatory framework for
into law along with the Affordable Care Act generics…
Generics Biosimilars
“Same (Identity)” = “Identical (Identity)”
Establish same active ingredient, Extensive structural and functional
strength, dosage form, route of characterization
administration, and condition of
use Pharmaceutical Therapeutic
Bioequivalence
Consider need for animal data to Equivalence Equivalence
assess toxicity
Demonstration of bioequivalence
Clinical studies to compare clinical Same active Same rate & Interchangeability
immunogenicity and PK/PD ingredients, extent of Rating
dosage form, absorbance &
 Sufficient to demonstrate that the product is
“highly similar” to the reference product and administration availability at
safe, pure, and potent for one or more route & strength site (80-125%)
approved conditions of use PE = Pharmaceutical Equivalence
BE = Bioequivalence
 FDA has discretion to determine that certain
studies not required
TE = Therapeutic Equivalence
“Same” Structure = “Same” Function
Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf.
Accessed 24 January 2013. Steven Kozlowski, M.D. Director Office of Biotechnology Products/OPS/CDER. Available at http://www.biosimilarstoday.com/Kozlowski.pdf

Grampp, Biosimilars—Scientific and Regulatory Considerations. 13 Grampp, Biosimilars—Scientific and Regulatory Considerations. 14
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FDA recommends a “Totality of Evidence” and a Demonstration of biosimilarity is the first step -
stepwise approach for biosimilar development interchangeability has additional requirements
Safety, Efficacy, and • The FDA will consider the totality of evidence
Clinical Immunogenicity provided3 Approved as an
studies1 One study to inform Approved as a biosimilar
immunogenicity and will – Comparative assessment of the structure interchangeable biologic
likely need at least one and function
clinical study in a
Clinical sensitive population to – Nonclinical evaluation
confirm safety
Pharm. and efficacy2 – Human PK/PD
(PK/PD) – Clinical immunogenicity Additional evidence is needed to demonstrate interchangeability1
– Clinical safety and efficacy, as needed Can be expected to produce the same clinical result as the reference
product in any given patient
Nonclinical
• The purpose of the biosimilar development AND
program is to demonstrate that the biosimilar For a product that is administered more than once, there is no additional
is highly similar to the reference product and risk in terms of safety or diminished efficacy as a result of switching
Analytical not to independently establish its safety and between the biosimilar and the reference product compared with using
Characterization effectiveness3 the reference product alone
(Structure & Function
• The type and extent of analyses and testing
Assessment)
that are needed to demonstrate biosimilarity
will be determined on a case-by-case basis3 • The United States is the only country with a specific definition for an interchangeable biologic2
FDA, Food and Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics.
• Studies needed to obtain the interchangeability designation are not yet determined by the FDA2
1. Kozlowski S. Presented at: Biotechnology Technology Summit; June 13, 2014; Rockville, MD.
https://www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski%20-%20Biomanufacturing%20Summit.pdf. Accessed February 5, 2015. FDA, Food and Drug Administration.
2. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2015. 1. Patient Protection and Affordable Care Act. 2009. http://www.gpo.gov/fdsys/pkg/BILLS-111hr3590pp/pdf/BILLS-111hr3590pp.pdf. Accessed April 30, 2015.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed April 30, 2015.
2. Camacho L, et al. Cancer Med. 2014;3:889-899.
3. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015.
15 Grampp, Biosimilars—Scientific and Regulatory Considerations. 16
MPhA Meeting January 31, 2016

Amgen Corporate Template 4

 Summary

The US pathway for approval of biosimilars was

signed into law along with the Patient Protection
and Affordable Care Act

A totality of evidence will be considered when

evaluating a biosimilar product for approval

Determination of interchangeability requires DEVELOPMENT OF

additional evidence BIOSIMILARS

Grampp, Biosimilars—Scientific and Regulatory Considerations. 17 Grampp, Biosimilars—Scientific and Regulatory Considerations. 18
MPhA Meeting January 31, 2016 MPhA Meeting January 31, 2016

Biosimilar manufacturers start with no Biosimilar development requires reverse engineering,

knowledge of the reference product starting with reference product characterization

Attributes related to the amino acid

sequence and all post-translational Biological and functional
modifications, including glycans activities, including receptor binding
Primary and immunochemical properties
structure
Integrity of the secondary,
• Purchase and analyze reference product tertiary, and quaternary
? • Determine amino acid sequence
structure Higher
order
structure
Biological
function
Product-related Degradation
• Characterize product, including glycosylation substances and profiles denoting
impurities stability
• Understand structure–function Quantitative levels of
product variants and Stability Receptor
• Determine critical quality attributes their identities General
properties
binding and
immuno- Kinetics and thermodynamics
and
chemical
excipients properties of binding, related to functional
activity
Process-
Properties of the finished related
drug product, including strength
impurities
Impurities from host cells
and formulation and downstream process

Kozlowski S. Presented at: Biotechnology Technology Summit; June 13, 2014; Rockville, MD. Available at:
US Food and Drug Administration. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf. Accessed
https://www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski%20-%20Biomanufacturing%20Summit.pdf. Accessed February 2015.
September 2015.

Grampp, Biosimilars—Scientific and Regulatory Considerations. 19 Grampp, Biosimilars—Scientific and Regulatory Considerations. 20
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Amgen Corporate Template 5

 Biosimilar manufacturers create a unique cell A stepwise development program follows
line and a unique manufacturing process after reverse engineering

Known1 Unknown2 Analytics

Biosimilar?
 Cell line Originator BLA Biosimilar
 Growth media Cross
 Method of cell expansion reference
 Bioreactor conditions Clinical 3. Clinical
 Protein recovery conditions studies Biosimilar?
Compare Cross
DNA  Purification conditions structure and reference

sequence  Formulation methods function Nonclinical 2. Non-Clinical

 Reagents
 Reference standards
Analytical Biosimilar? 1. Quality
Characterization Cross reference –
(Structure & Function Prior findings of safety and Integrated Biosimilarity Exercise –
Quality, Safety and Efficacy
To reverse engineer a reference product, each Assessment) efficacy
biosimilar developer must create a manufacturing
process for that biologic de novo2
Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf.
Accessed 24 January 2013.
1. Mellstedt H et al. Ann Oncol 2008;19:411-419. 2. Roger SD. Nephrology (Carlton) 2006;11:341-346.

Grampp, Biosimilars—Scientific and Regulatory Considerations. 21 Grampp, Biosimilars—Scientific and Regulatory Considerations. 22
MPhA Meeting January 31, 2016 MPhA Meeting January 31, 2016

Stepwise assessment begins with extensive Comparisons assess alignment of many

structural and functional comparisons attributes, with emphasis on critical attribute

General properties1 Sample exercise: Biosimilar attributes

compared with reference product1
Primary structure2
• Foundational for biosimilar Biosimilar Biosimilar
vs US vs EU
development program High-order structure2 reference reference
• Involves structural and functional product product
characterization of reference Biological2
Attributes
product 91 93
matched
Product-related substances and impurities2
• Involves the determination of
Attributes not
differences in relevant critical Process-related impurities2 matched, but 4 2
attributes between biosimilar and not critical
Analytical reference product using Particles and aggregates1 Attributes not
Characterization appropriate analytical matched and 0 0
(Structure & Function Product degradation2 critical
methodology
Assessment)
Adapted from Foraker S, provided October 28, 2014, as part of an oral presentation and is qualified by such, containing forward-looking statements, and actual
results may vary materially; Amgen disclaims any duty to update.
ABP, Amgen biosimilar product; EU, European Union; US, United States.
1. Adapted from Foraker S. http://investors.amgen.com/phoenix.zhtml?c=61656&p=irol-presentations. Accessed March 5, 2015. 2. FDA. Guidance for Industry: Quality
Considerations in Demonstrating Biosimilarity to a Reference Protein Product. 2012.
FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf. Accessed February 6, 2015.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015.
Grampp, Biosimilars—Scientific and Regulatory Considerations. 23 Grampp, Biosimilars—Scientific and Regulatory Considerations. 24
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Amgen Corporate Template 6

 Toxicity assessments based on data Clinical pharmacology studies are a
from animal studies are useful critical part of demonstrating biosimilarity
• Comparative human PK and PD studies are fundamental
components in demonstrating there no clinically meaningful
differences between reference and biosimilar1

• PK studies should demonstrate similar exposure over time and

• Animal toxicity data are useful when PD studies should demonstrate similar effect on clinically
uncertainties remain about safety of relevant PD measure(s) related to efficacy or safety concerns1
biosimilar after extensive structural Clinical
• Important PK parameters that are commonly studied include
and functional characterization Pharm. AUC and Cmax2
(PK/PD)
Nonclinical • Not warranted if biosimilar has been Example of PK of biosimilar that is highly
demonstrated to be highly similar to similar to that of the reference3
reference through analytical

concentration, µg/mL
Mean (±SD) serum
characterization

Biosimilar
Reference

Figure reproduced from Park W, et al. Ann Rheum Dis. 2013;72:1605-1612. With permission from BMJ Publishing Group Ltd.
FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
AUC, area under the concentration-time curve; Cmax , maximum concentration; PD, pharmacodynamics; PK, pharmacokinetics; SD, standard deviation. aBiosimilar N=113.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015.
1. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015. 2. FDA. Guidance for Industry: Clinical Pharmacology Data to Support a
Grampp, Biosimilars—Scientific and Regulatory Considerations. 25 Demonstration of Biosimilarity to a Reference Product. 2014. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf.
26 3. Park W, et al. Ann Rheum Dis.
MPhA Meeting January 31, 2016 2013;72:1605-1612.

Immunogenicity studies are critical for Comparative clinical safety and efficacy
establishing biosimilarity assessments may address residual uncertainties
Safety, Efficacy, and
Immunogenicity Clinical Studies
One clinical study in Factors that affect the type and
Clinical a sensitive population (Safety,
extent of clinical efficacy and safety
Studies
to inform
immunogenicity1 • The goal of immunogenicity studies is Efficacy)1 studies needed2
to establish that there are no clinically
meaningful differences in incidence and • Nature and complexity of the
Clinical
severity of human immune response
Clinical reference
Pharm.
between the biosimilar and reference Pharm. • Mechanism of action of reference and
PK/PD (PK/PD) disease pathology
product2
• Extent of clinical experience with the
reference and its therapeutic class
Nonclinical • Extent to which differences in
• Immunogenicity can be tested during structure and function studies predict
clinical safety and efficacy studies, differences in clinical outcomes
including PK/PD studies1 Analytical • Extent to which PK and PD studies
• Studies should be conducted in sensitive Characterization predict clinical outcomes (eg, are
population2 (Structure & Function sensitive PD markers available)
• Studies should include assessment of Assessment)
binding and neutralizing antibodies2
PD, pharmacodynamics; PK, pharmacokinetics.
PD, pharmacodynamics; PK, pharmacokinetics.
1. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2015. 1. Kozlowski S. Presented at: Biotechnology Technology Summit; June 13, 2014; Rockville, MD.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015. https://www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski%20-%20Biomanufacturing%20Summit.pdf. Accessed February 5, 2015.
2. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012. 2. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015.
27 28

Amgen Corporate Template 7

 Indication extrapolation is important to
Clinical confirmation: safety and efficacy biosimilar development
• A proposed biosimilar product may be licensed in one or
Clinical
Studies
(Safety, • The goal is to demonstrate that the biosimilar has neither
Efficacy)
decreased nor increased activity compared with the
more additional conditions of use for which the reference
reference product and has similar immunogenicity product is licensed, without additional clinical trials, if
appropriate scientific justification is provided
Study design • Two-sided test to demonstrate equivalence; with an appropriate equivalence • Extrapolation is not automatic
margin
– A one-sided noninferiority design more appropriate in certain Reference product studies Biosimilar studies
circumstances
Endpoints and • Clinically relevant and sensitive in detecting clinically meaningful differences
study population • Selected by considering comorbidities and effect on disease state (eg,
immunosuppressed)
RA AS RA + PsO
+ +
Important • Clinical trial should allow PsO + CD
considerations – Sufficient exposure
– Detection of relevant safety signals + + Extrapolated indications
– Detection of clinically meaningful differences in effectiveness and safety PsA UC

FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015.
PsA + AS + CD + UC
AS, ankylosing spondylitis; CD, Crohn’s disease; PsA, psoriatic arthritis; PsO, psoriasis; RA, rheumatoid arthritis; UC, ulcerative colitis.
US Food and Drug Administration. Available at:
Grampp, Biosimilars—Scientific and Regulatory Considerations. 29 30
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128.pdf. Accessed September 2015.
MPhA Meeting January 31, 2016

FDA recommendations address Summary:

considerations related to extrapolation Pillars of Biosimilar Development
Considerations1 FDA recommendations2
• Extrapolation is considered on case-by-case basis Biosimilar development starts with reverse engineering of the reference product quality
• When MOA is not fully understood, separate attributes
clinical trials in each indication are likely
Potential for distinct MOA in each Physiochemical and functional characterization of both the reference and the biosimilar
necessary
therapeutic indication • Biological data covering all functional aspects of is foundational to stepwise development
agent, demonstrating high similarity to reference,
is required Comparative human PK and PD studies demonstrating absence of clinically meaningful
differences between reference and biosimilar are critical to establishing biosimilarity
Variable optimal doses for efficacy • Data are produced using patient population and Immunogenicity testing demonstrating no clinically meaningful differences in incidence
or safety profiles in different clinical endpoint most sensitive to detect clinically and severity is required
patient groups meaningful differences in efficacy and safety
It is likely that at least one clinical study in a sensitive population is needed to confirm
safety and efficacy and inform immunogenicity
Influence of individual patient • Careful consideration must be given to
characteristics on treatment comorbidities/concomitant medications and Appropriate scientific justification is required to allow extrapolation of indications of use
response intersubject variability for which the reference is licensed

FDA, Food and Drug Administration; MOA, mechanism of action.

1. Dörner T, et al. Ann Rheum Dis. 2013;72:322-328. 2. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. FDA, Food and Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics.
2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015.
Grampp, Biosimilars—Scientific and Regulatory Considerations. 31 Grampp, Biosimilars—Scientific and Regulatory Considerations. 32
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Amgen Corporate Template 8

 Ongoing pharmacovigilance is important
for biologics and biosimilars

Robust post-marketing safety monitoring is important to

ensure similar safety and effectiveness between the biosimilar
and the reference drug

Safety monitoring should take into account the safety or

effectiveness concerns associated with reference product

Safety monitoring should have the ability to differentiate

POST-APPROVAL CONSIDERATIONS between adverse events associated with the proposed
biosimilar product vs those associated with the reference drug
or other biosimilars

FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2012.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015.

33 Grampp, Biosimilars—Scientific and Regulatory Considerations. 34

MPhA Meeting January 31, 2016

Why the practitioner needs to know Proximal agent is

not always the
what product a patient received casual agent! Class effect vs. product specific effect
“[C]ompanies will make manufacturing-related
changes to biologics periodically … and even Requires
small changes could affect safety or efficacy.”
– FDA1
Safety
• Sensitivity and Monitoring
complexity • Access to accurate and
• Manufacturing • Immune response complete medication
• Potential “drift” histories
changes
between products
Medical
Variability
Records
Justifies
Doctors CVS for
Refill #1
Office

Walgreens
Refill #2
Patient Record

Independent
1. Kozlowski S et al. N Engl J Med. 2011;365:385-388. pharmacy
Refill #3

Grampp, Biosimilars—Scientific and Regulatory Considerations. 35 Source: Casadevall Nicole, Immune-response and adverse reactions: PRCA case example. Presentation to EMA Nov, 36
2009. Available at
MPhA Meeting January 31, 2016 http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2009/11/WC500011064.pdf

Amgen Corporate Template 9

 Interchangeability will require additional In the US, state regulations govern
evidence beyond approval as a biosimilar automatic substitution

Additional evidence is needed to

demonstrate interchangeability1
FDA approves a Automatic State pharmacy
Can be expected to produce the same substitution
clinical result as the reference product biologic as practice laws allow
of an
in any given patient interchangeable interchangeable for substitution of
AND Approved, with the reference biologic is an interchangeable
Approved For a product that is administered more interchangeable product1 allowed biologic2
biosimilar than once, there is no additional risk to biosimilar
safety or efficacy as a result of
switching between the biosimilar and
the reference product

The US is the only country with a specific definition

of an interchangeable biologic 1. US Food and Drug Administration.
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm2
41718.htm. Accessed February 2015. 2. NCSL. State Laws and Legislation Related to Biologic Medications and Substitution of Biosimilars. 2014.
1. US Food and Drug Administration. Available at: http://www.ncsl.org/documents/health/Biologics_BiosimilarsNCSLReport_July_2014.pdf. Accessed April 4, 2015.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM444661.pdf. Accessed September 2015.

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Summary

Ongoing safety monitoring is critical to ensuring patient safety.

FDA has proposed a system of distinguishable nonproprietary names to help

facilitate accurate and timely adverse event reporting.

FDA determines interchangeability and states determine the terms of

pharmacy substitution of biologics

THANKS!

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Amgen Corporate Template 10