Biosimilars—Scientific and
Regulatory Considerations
Gustavo Grampp
Regulatory Policy Director, Amgen
Presented at Maryland Pharmacists Association meeting January 31, 2016
2
Program objectives
1. Review complexities of biologics and differences from chemical drugs
2. Introduce the US biosimilar regulatory framework
3. Learn about biosimilar development including design, analytical studies, and clinical studies
4. Discuss post-approval considerations including pharmacovigilance, interchangeability, and substitution
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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INTRODUCTION TO
BIOLOGICS
4
What is a biologic?
• Biologics are large protein-based therapeutics
– Biologics can include antibodies, recombinant proteins, or
fusion proteins
Monoclonal antibody
Neiderwieser D et al. Eur J Haematol 2011;86:277-288.
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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What is a biologic?
• Biologics are more complex in structure and function
than chemical drugs
Monoclonal antibody1
~150 kDa
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.
Up to 1000×
larger1,2
Acetylsalicylic acid2
~0.18 kDa
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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What is a biologic?
• Biologics are more complex in structure and function
than chemical drugs
Acetylsalicylic acid Monoclonal antibody
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.
Simple,2
well-defined3
Complex,
with post-translational
modifications1
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Patient
treatment2
Formulation,1 fill,2
and finish2
Characterization
and stability2
Transfection of
DNA into host cell1
Isolation2 and purification1
Cell culture
and expansion1
Cell line
selection and
development1
Refrigeration,2
storage,2 and
transport1
Manufacturer establishes a
unique master cell bank1
Biologics are made by living cells
through well-controlled processes
1. Kresse GB. Eur J Pharm Biopharm. 2009;72:479-486. 2. Sharma BG. EJHP Practice. 2007;13:54-56.
A typical biotechnology manufacturing process includes multiple stages
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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So what is a biosimilar?
• According to the US FDA, a biosimilar is a biological
product that is highly similar to the reference product
• There are no clinically meaningful differences in terms
of:
– Safety
– Purity
– Potency
FDA, Food and Drug Administration.
US Food and Drug Administration. Available at: http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128.pdf. Accessed
September 2015.
Differences between biosimilars and reference biologics
are expected, but must not be clinically meaningful
In other words:
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Each biosimilar is unique because of
differences in manufacturing
Known DNA sequence Unique manufacturing Unique biosimilar
1. Roger SD. Nephrology (Carlton) 2006;11:341-346. 2. Mellstedt H et al. Ann Oncol 2008;19:411-419.
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Biosimilars are fundamentally different
from generics
MW, molecular weight.
1. Aspirin comprehensive prescribing information. Available at: www.fda.gov/ohrms/dockets/ac/03/briefing/4012B1_03_Appd%201Professional%20Labeling.pdf.
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.
Monoclonal
antibody
Large2
MW = ~150,000 Da3
Each manufactured in a
unique living cell line2
Similar but not identical
copy can be made2
Sensitive to storage
and handling
conditions2
Acetylsalicylic acid1
Small2
MW = 180 Da1
Predictable chemical
process
Identical copy can be
made2
Relatively stable2
Acetylsalicylic acid1
Lower potential2
Simple5 and
well defined2
Easy to fully
characterize6
Monoclonal
antibody
Higher potential2
Complex with many
options for post-
translational
modification4
Difficult to
characterize fully
owing to a mixture of
related molecules6
STRUCTURE
CHARACTERIZATIONS
IMMUNOGENICITY
SIZE
MANUFACTURING
STABILITY
Biosimilars Generics Biosimilars Generics
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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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 complexity, manufacturing and sensitivity
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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REGULATORY FRAMEWORKS
13
The US biosimilars pathway was signed
into law along with the Affordable Care Act
Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf.
Accessed 24 January 2013.
Extensive structural and functional characterization
Sufficient to demonstrate that the product is “highly similar” to the reference product and safe, pure, and potent for one or more approved conditions of use
FDA has discretion to determine that certain studies not required
Consider need for animal data to assess toxicity
Clinical studies to compare clinical immunogenicity and PK/PD
Biosimilars
Establish same active ingredient, strength, dosage form, route of administration, and condition of
use
Demonstration of bioequivalence
Generics
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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In contrast to the regulatory framework for
generics…
Same active
ingredients,
dosage form,
administration
route & strength
Same rate &
extent of
absorbance &
availability at
site (80-125%)
Interchangeability
Rating
Steven Kozlowski, M.D. Director Office of Biotechnology Products/OPS/CDER. Available at http://www.biosimilarstoday.com/Kozlowski.pdf
PE = Pharmaceutical Equivalence
BE = Bioequivalence
TE = Therapeutic Equivalence “Same” Structure = “Same” Function
“Same (Identity)” = “Identical (Identity)”
Pharmaceutical
Equivalence Bioequivalence
Therapeutic
Equivalence
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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• The FDA will consider the totality of evidence
provided3
– Comparative assessment of the structure
and function
– Nonclinical evaluation
– Human PK/PD
– Clinical immunogenicity
– Clinical safety and efficacy, as needed
• The purpose of the biosimilar development
program is to demonstrate that the biosimilar
is highly similar to the reference product and
not to independently establish its safety and
effectiveness3
• The type and extent of analyses and testing
that are needed to demonstrate biosimilarity
will be determined on a case-by-case basis3
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.
2. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2015.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed April 30, 2015.
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.
Clinical Pharm. (PK/PD)
Nonclinical
Analytical Characterization (Structure & Function
Assessment)
Safety, Efficacy, and
Immunogenicity
One study to inform
immunogenicity and will
likely need at least one
clinical study in a
sensitive population to
confirm safety
and efficacy2
Clinical
studies1
FDA recommends a “Totality of Evidence” and a
stepwise approach for biosimilar development
FDA, Food and Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics.
16
1. Patient Protection and Affordable Care Act. 2009. http://www.gpo.gov/fdsys/pkg/BILLS-111hr3590pp/pdf/BILLS-111hr3590pp.pdf. Accessed April 30, 2015.
2. Camacho L, et al. Cancer Med. 2014;3:889-899.
• The United States is the only country with a specific definition for an interchangeable biologic2
• Studies needed to obtain the interchangeability designation are not yet determined by the FDA2
FDA, Food and Drug Administration.
Approved as a biosimilar Approved as an
interchangeable biologic
Additional evidence is needed to demonstrate interchangeability1
Can be expected to produce the same clinical result as the reference product in any given patient
AND
For a product that is administered more than once, there is no additional risk in terms of safety or diminished efficacy as a result of switching between the biosimilar and the reference product compared with using
the reference product alone
Demonstration of biosimilarity is the first step -
interchangeability has additional requirements
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
17
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 additional evidence
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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DEVELOPMENT OF
BIOSIMILARS
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Biosimilar manufacturers start with no
knowledge of the reference product
• Purchase and analyze reference product
• Determine amino acid sequence
• Characterize product, including glycosylation
• Understand structure–function
• Determine critical quality attributes
?
Kozlowski S. Presented at: Biotechnology Technology Summit; June 13, 2014; Rockville, MD. Available at:
https://www.ibbr.umd.edu/sites/default/files/public_page/Kozlowski%20-%20Biomanufacturing%20Summit.pdf. Accessed February 2015.
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Biosimilar development requires reverse engineering,
starting with reference product characterization
Stability
Primary structure
Biological function
Receptor binding and
immuno-chemical properties
Process-related
impurities
General properties
and excipients
Higher order
structure
Product-related
substances and
impurities
Attributes related to the amino acid
sequence and all post-translational
modifications, including glycans
Biological and functional
activities, including receptor binding
and immunochemical properties
Degradation
profiles denoting
stability
Quantitative levels of
product variants and
their identities
Kinetics and thermodynamics
of binding, related to functional
activity
Integrity of the secondary,
tertiary, and quaternary
structure
Properties of the finished
drug product, including strength
and formulation
Impurities from host cells
and downstream process
US Food and Drug Administration. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf. Accessed
September 2015.
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Biosimilar manufacturers create a unique cell
line and a unique manufacturing process
Known1 Analytics Unknown2
DNA sequence
Cell line
Growth media
Method of cell expansion
Bioreactor conditions
Protein recovery conditions
Purification conditions
Formulation methods
Reagents
Reference standards
Compare structure and
function
To reverse engineer a reference product, each
biosimilar developer must create a manufacturing
process for that biologic de novo2
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.
MPhA Meeting January 31, 2016
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Biosimilar
1. Quality
Cross reference
2. Non-Clinical
3. Clinical
Cross reference
Cross reference – Prior findings of safety and
efficacy
Integrated Biosimilarity Exercise – Quality, Safety and Efficacy
Originator BLA
A stepwise development program follows
after reverse engineering
Food and Drug Administration. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf.
Accessed 24 January 2013.
Clinical studies
Nonclinical
Analytical Characterization (Structure & Function
Assessment)
Biosimilar?
Biosimilar?
Biosimilar?
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Stepwise assessment begins with extensive
structural and functional comparisons
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.
Analytical Characterization (Structure & Function
Assessment)
• Foundational for biosimilar
development program
• Involves structural and functional
characterization of reference
product
• Involves the determination of
differences in relevant critical
attributes between biosimilar and
reference product using
appropriate analytical
methodology
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Comparisons assess alignment of many
attributes, with emphasis on critical attribute
Primary structure2
High-order structure2
Biological2
Product-related substances and impurities2
Process-related impurities2
Product degradation2
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.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291134.pdf. Accessed February 6, 2015.
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.
Sample exercise: Biosimilar attributes
compared with reference product1
Biosimilar
vs US
reference
product
Biosimilar
vs EU
reference
product
Attributes
matched 91 93
Attributes not
matched, but
not critical
4 2
Attributes not
matched and
critical
0 0
General properties1
Particles and aggregates1
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Toxicity assessments based on data
from animal studies are useful
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.
• Animal toxicity data are useful when
uncertainties remain about safety of
biosimilar after extensive structural
and functional characterization
• Not warranted if biosimilar has been
demonstrated to be highly similar to
reference through analytical
characterization
Nonclinical
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
26
Clinical Pharm. (PK/PD)
Clinical pharmacology studies are a
critical part of demonstrating biosimilarity
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
Demonstration of Biosimilarity to a Reference Product. 2014. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM397017.pdf. 3. Park W, et al. Ann Rheum Dis.
2013;72:1605-1612.
• 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
PD studies should demonstrate similar effect on clinically
relevant PD measure(s) related to efficacy or safety concerns1
• Important PK parameters that are commonly studied include
AUC and Cmax2
Biosimilar
Reference
Example of PK of biosimilar that is highly
similar to that of the reference3
Me
an
(±S
D)
se
rum
co
nce
ntr
ati
on
, µ
g/m
L
AUC, area under the concentration-time curve; Cmax, maximum concentration; PD, pharmacodynamics; PK, pharmacokinetics; SD, standard deviation. aBiosimilar N=113.
Figure reproduced from Park W, et al. Ann Rheum Dis. 2013;72:1605-1612. With permission from BMJ Publishing Group Ltd.
27
Immunogenicity studies are critical for
establishing biosimilarity
1. FDA. Guidance for Industry: Scientific Considerations in Demonstrating Biosimilarity to a Reference Product. 2015.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015.
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.
• The goal of immunogenicity studies is
to establish that there are no clinically
meaningful differences in incidence and
severity of human immune response
between the biosimilar and reference
product2
Safety, Efficacy, and
Immunogenicity
One clinical study in
a sensitive population
to inform
immunogenicity1
Clinical
Studies
• Immunogenicity can be tested during
clinical safety and efficacy studies,
including PK/PD studies1
• Studies should be conducted in sensitive
population2
• Studies should include assessment of
binding and neutralizing antibodies2
PD, pharmacodynamics; PK, pharmacokinetics.
Clinical Pharm. PK/PD
28
Comparative clinical safety and efficacy
assessments may address residual uncertainties
Clinical Pharm. (PK/PD)
Nonclinical
Analytical Characterization (Structure & Function
Assessment)
Clinical Studies
(Safety,
Efficacy)1
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.
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.
Factors that affect the type and extent of clinical efficacy and safety
studies needed2
• Nature and complexity of the reference
• Mechanism of action of reference and disease pathology
• Extent of clinical experience with the reference and its therapeutic class
• Extent to which differences in structure and function studies predict differences in clinical outcomes
• Extent to which PK and PD studies predict clinical outcomes (eg, are sensitive PD markers available)
PD, pharmacodynamics; PK, pharmacokinetics.
29
Clinical confirmation: safety and efficacy
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.
• The goal is to demonstrate that the biosimilar has neither
decreased nor increased activity compared with the
reference product and has similar immunogenicity
Clinical
Studies
(Safety,
Efficacy)
Study design • Two-sided test to demonstrate equivalence; with an appropriate equivalence
margin
– A one-sided noninferiority design more appropriate in certain
circumstances
Endpoints and
study population
• Clinically relevant and sensitive in detecting clinically meaningful differences
• Selected by considering comorbidities and effect on disease state (eg,
immunosuppressed)
Important
considerations
• Clinical trial should allow
– Sufficient exposure
– Detection of relevant safety signals
– Detection of clinically meaningful differences in effectiveness and safety
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Indication extrapolation is important to
biosimilar development
• A proposed biosimilar product may be licensed in one or
more additional conditions of use for which the reference
product is licensed, without additional clinical trials, if
appropriate scientific justification is provided
• Extrapolation is not automatic
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:
http://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm291128.pdf. Accessed September 2015.
Reference product studies
RA
PsA
Biosimilar studies
Extrapolated indications
RA PsO +
+
+
AS CD +
AS
PsO CD
UC
+
+
PsA + UC +
+
31
FDA recommendations address
considerations related to extrapolation
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.
2012. http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM291128.pdf. Accessed February 7, 2015.
Potential for distinct MOA in each
therapeutic indication
Variable optimal doses for efficacy
or safety profiles in different
patient groups
Influence of individual patient
characteristics on treatment
response
• Extrapolation is considered on case-by-case basis
• When MOA is not fully understood, separate
clinical trials in each indication are likely
necessary
• Biological data covering all functional aspects of
agent, demonstrating high similarity to reference,
is required
• Data are produced using patient population and
clinical endpoint most sensitive to detect clinically
meaningful differences in efficacy and safety
• Careful consideration must be given to
comorbidities/concomitant medications and
intersubject variability
Considerations1 FDA recommendations2
FDA, Food and Drug Administration; MOA, mechanism of action.
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Summary:
Pillars of Biosimilar Development
Biosimilar development starts with reverse engineering of the reference product quality attributes
Physiochemical and functional characterization of both the reference and the biosimilar is foundational to stepwise development
Comparative human PK and PD studies demonstrating absence of clinically meaningful differences between reference and biosimilar are critical to establishing biosimilarity
Immunogenicity testing demonstrating no clinically meaningful differences in incidence and severity is required
It is likely that at least one clinical study in a sensitive population is needed to confirm safety and efficacy and inform immunogenicity
Appropriate scientific justification is required to allow extrapolation of indications of use for which the reference is licensed
FDA, Food and Drug Administration; PD, pharmacodynamics; PK, pharmacokinetics.
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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POST-APPROVAL CONSIDERATIONS
34
Ongoing pharmacovigilance is important
for biologics and 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.
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 between adverse events associated with the proposed biosimilar product vs those associated with the reference drug or other biosimilars
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Why the practitioner needs to know
what product a patient received
• Sensitivity and complexity
• Manufacturing changes
Variability
• Immune response
• Potential “drift” between products
Safety Monitoring
• Access to accurate and complete medication histories
Medical Records
Requires
Justifies
“[C]ompanies will make manufacturing-related
changes to biologics periodically … and even
small changes could affect safety or efficacy.”
– FDA1
CVS for
Refill #1
Walgreens Refill #2
Independent pharmacy Refill #3
Doctors
Office
Patient Record
1. Kozlowski S et al. N Engl J Med. 2011;365:385-388.
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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Class effect vs. product specific effect
Source: Casadevall Nicole, Immune-response and adverse reactions: PRCA case example. Presentation to EMA Nov, 2009. Available at
http://www.ema.europa.eu/docs/en_GB/document_library/Presentation/2009/11/WC500011064.pdf
Proximal agent is not always the casual agent!
37
Additional evidence is needed to demonstrate interchangeability1
Can be expected to produce the same clinical result as the reference product
in any given patient
AND
For a product that is administered more than once, there is no additional risk to
safety or efficacy as a result of switching between the biosimilar and
the reference product
Interchangeability will require additional
evidence beyond approval as a biosimilar
1. US Food and Drug Administration. Available at:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM444661.pdf. Accessed September 2015.
Approved
biosimilar
Approved,
interchangeable
biosimilar
The US is the only country with a specific definition
of an interchangeable biologic
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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In the US, state regulations govern
automatic substitution
FDA approves a
biologic as
interchangeable
with the reference
product1
State pharmacy
practice laws allow
for substitution of
an interchangeable
biologic2
Automatic
substitution
of an
interchangeable
biologic is
allowed
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.
http://www.ncsl.org/documents/health/Biologics_BiosimilarsNCSLReport_July_2014.pdf. Accessed April 4, 2015.
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
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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
Grampp, Biosimilars—Scientific and Regulatory Considerations.
MPhA Meeting January 31, 2016
40
THANKS!
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