Biosimilar and Interchangeable Products in

the United States:

Scientific and Regulatory Concepts

PQRI Biopharmaceutics Technical Committee Webinar

September 16, 2020

M. Stacey Ricci, MEng, ScD

Director, Scientific Review Staff (Acting)
Office of Therapeutic Biologics and Biosimilars
OND/CDER/FDA
What are Biosimilars?

 Biosimilars are FDA-approved, biologic

medications that are compared to
another medication – the original biologic
(also called a reference product)

 Biosimilars are made with the same types

of natural sources as the original biologic
they were compared to – and provide the
same treatment benefits.
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 What are Interchangeable Biosimilars?
An interchangeable biosimilar product can be substituted for the
reference product at pharmacies without the intervention
of the prescribing health care provider.

Pharmacy Substitution

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 Regulatory Background
 An application submitted under section 351(a) of the PHS Act is a “stand-alone”
application that must contain all information and data necessary to demonstrate
that the proposed product is safe, pure and potent (safe and effective).

 The Biologics Price Competition and Innovation Act of 2009 (BPCI Act) created an
abbreviated licensure pathway for biological products shown to be biosimilar to
or interchangeable with an FDA-licensed reference product.

The abbreviated licensure pathway means manufacturer may rely, in part, on

FDA’s previous determination for the reference product.

Generally, biosimilar manufacturers do not need to conduct as many

expensive and lengthy clinical trials, potentially leading to faster access to
these products. However, the biosimilar or interchangeable product is still
subject to FDA’s rigorous approval standards.
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 Demonstrating Biosimilarity

Biosimilar or Biosimilarity means:

 that the biological product is highly similar to
the reference product notwithstanding minor
differences in clinically inactive components;
and

 there are no clinically meaningful differences

between the biological product and the
reference product in terms of the safety, purity,
and potency of the product.

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 Demonstrating Biosimilarity
A 351(k) application must include information demonstrating that the biological
product:
• Is biosimilar to a reference product;
• Utilizes the same mechanism(s) of action for the proposed condition(s) of
use -- but only to the extent the mechanism(s) are known for the reference
product;
• Condition(s) of use proposed in labeling have been previously approved for
the reference product;
• Has the same route of administration, dosage form, and strength as the
reference product; and
• Is manufactured, processed, packed, or held in a facility that meets
standards designed to assure that the biological product continues to be
safe, pure, and potent. 6
 Demonstrating Biosimilarity
• Approval of a biosimilar product is based on the totality of the evidence
submitted by the applicant to provide an overall assessment that the
proposed product is biosimilar to the reference product.
• A demonstration supporting biosimilarity will be based upon data from:
analytical studies, animal studies, if any; and clinical study or studies.
• Nature and scope of clinical studies will depend on the extent of residual
uncertainty about the biosimilarity of the two products after conducting
structural and functional characterization and relevant animal studies, if any.

Analytical studies Animal studies A clinical study FDA Review FDA Post-Market Safety
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or studies Monitoring

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Totality of the evidence
 Comparative Analytical Data - The Foundation of a
Biosimilar Development Program
Extensive structural and functional
characterization
– A biosimilar product with similar
structure and function to the
reference product should behave like
the reference product (i.e., have
similar efficacy and safety as the
reference product)

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Can Most Biologics be Copied Exactly? No

 Biologics are generally large, complex molecules

 Most biologics are mixtures of variants
 Using advanced scientific analyses, molecular
patterns and profiles emerge
 Biosimilars try to match the patterns and
variations of the reference product
 Both the reference product and biosimilar contain
these variants and try to keep a consistent mix

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 Comparative Analytical Assessment
 FDA draft guidance for industry “Development of Therapeutic
Protein Biosimilars: Comparative Analytical Assessment and Other
Quality Considerations” describes recommendations for the design
and evaluation of comparative analytical studies

 This guidance includes considerations for the development of a

comparative analytical assessment plan, using a stepwise approach,
to support a demonstration of biosimilarity

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 Comparative Analytical Assessment
Guidance provides clarity and flexibility for developers on:
• Analytical approaches to evaluating product structure and
function
• Updated recommendations for collection and analysis of
comparative analytical similarity data
• Receptiveness to considering alternative approaches proposed
by sponsors for the analysis of analytical similarity data
• Aspects of the chemistry, manufacturing, and controls (CMC)
portion (e.g., characterization, adventitious agent safety testing,
process controls, specifications, and stability) of the marketing
application
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 Comparative Analytical Assessment
• Comparative assessment of multiple physicochemical and biological attributes
• Assays must be fit for purpose – able to detect differences if they exist
• Analyze multiple lots of the reference product and proposed biosimilar for each
attribute:
– Primary amino acid sequence
– Biological activity - evaluation of attributes that affect known or presumed mechanism(s) of
action
– Post-translational modifications (glycosylation, phosphorylation, etc.)
– Protein folding (higher order structure)
– Heterogeneity (charge, size, aggregates, etc.)
– Thermal and temporal stability
– Impurities
– Others
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 Role of Clinical Studies
• The nature and scope of clinical studies will
depend on the extent of residual uncertainty
about the biosimilarity of the two products
after conducting structural and functional
characterization and, where relevant, animal
studies.
• See these FDA Guidance for Industry for
recommendations on clinical studies
– Scientific Considerations in Demonstrating
Biosimilarity to a Reference Product (2015)
– Clinical Pharmacology Data to Support a
Demonstration of Biosimilarity to a Reference
Product (2016)
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 Comparative Human PK and PD Data
• PK and/or PD is generally considered the most sensitive clinical
study/assay in which to assess for differences between
products, should they exist
– PK similarity in an adequately sensitive population to
detect any differences
– PD similarity using PD measure(s) that reflects the
mechanism of action (MOA) or reflects the biological
effect(s) of the drug,
• PK and PD similarity data supports a demonstration of
biosimilarity with the assumption that similar exposure (and
pharmacodynamic response, if applicable) will provide similar
efficacy and safety (i.e., an exposure-response relationship
exists)
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 Comparative Clinical Study
• A comparative clinical study for a biosimilar
development program should be designed to investigate
whether there are clinically meaningful differences in
safety and efficacy between the proposed product and
the reference product.
• Population, endpoint, sample size and study duration
should be adequately sensitive to detect differences,
should they exist.
• Typically, an equivalence design would be used, but
other designs may be justified
• Assessment of immunogenicity is expected

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 Extrapolation
• A biosimilar product can approved for one or more
additional conditions of use for which the reference
product is licensed based on extrapolation
• FDA guidance outlines factors to consider, including:
– MoA in each proposed condition of use
– PK and biodistribution in different patient populations
– Immunogenicity in different patient populations
– Differences in expected toxicities in each condition of use and
patient population
– Any other factor affecting safety or efficacy in each proposed
condition of use
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 Extrapolation Considerations:
“Stand-alone” Drug Development
Clinical Clinical Clinical Clinical
Safety & Efficacy Safety & Efficacy Safety & Efficacy Safety & Efficacy

Clinical Pharmacology
Indication 2 Indication 3 Indication 4
Non-clinical

Analytical

Indication 1

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 Extrapolation Considerations:
“Stand-alone” vs. Biosimilar Development
Clinical Clinical Clinical Clinical
Safety & Safety & Safety & Safety &
Efficacy Efficacy Efficacy Efficacy
Clinical Pharmacology
Indication 2 Indication 3 Indication 4
Non-clinical

Analytical

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 Interchangeability
FDA guidance, “Considerations in Demonstrating Interchangeability
With a Reference Product,” provides FDA’s current thinking on scientific
considerations in demonstrating that a proposed biological product is
interchangeable with a reference product.
Outlines a stepwise approach to generate data
Totality-of-the-evidence approach– no “one-size fits all” assessment
Retained flexibility to provide space for the science in this area to
evolve and for FDA to provide targeted advice on efficient study design
in the context of product-specific meetings with prospective applicants.

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Demonstrating Interchangeable Biosimilarity
1. The proposed interchangeable must be biosimilar to the
reference product.
2. The application must demonstrate that the proposed
interchangeable “can be expected to produce the same
clinical result as the reference product in any given
patient.”
– This will likely not involve additional clinical studies other than
those necessary to support other elements of demonstrating
interchangeability.
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 Demonstrating Interchangeable
Biosimilarity, cont’d
3. For products administered more than once to a patient,
information sufficient to show that “the risk in terms of
safety or diminished efficacy of alternating or switching
between use of the biological product and the reference
product is not greater than the risk of using the reference
product without such alternation or switch.”
– To evaluate the risk, in terms of safety and diminished efficacy,
of alternating or switching between the products, applications
generally will include data from a switching study or studies in
one or more appropriate conditions of use.
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 Demonstrating Interchangeable
Biosimilarity, cont’d
• Switching studies: Guidance outlines considerations for study design,
including endpoints, design and analysis, study population, condition(s) of
use, and routes of administration to be studied.
– Option for sponsor to provide justification to FDA of why such data is
not needed.
– Switching studies generally not needed for biological products that are
not intended to be administered to an individual more than once.

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The Promise of Biosimilar and
Interchangeable Products

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 FDA Approved Biosimilars
Year Biosimilars Approved by FDA Reference Approved = 28 Marketed = 17
2020 Hulio (adalimumab-fkjb) Nyvepria (pegfilgrastim-apgf) Product
2019 Ontruzant (trastuzumab-dttb) Ruxience (rituximab-pvvr)
Herceptin 5 5
Trazimera (trastuzumab-qyyp) Hadlima (adalimumab-bwwd)
Eticovo (etanercept-ykro) Ziextenzo (pegfilgrastim-bmez) Humira 6 0
Kanjinti (trastuzumab-anns) Abrilada (adalimumab-afzb)
Remicade 4 2
Zirabev (bevacizumab-bvzr) Avsola (infliximab-axxq)
2018 Retacrit (epoetin alfa-epbx) Udenyca (pegfilgrastim-cbqv) Neulasta 4 3
Fulphila (pegfilgrastim-jmdb) Truxima (rituximab-abbs)
Nivestym (filgrastim-aafi) Herzuma (trastuzumab-pkrb) Neupogen 2 2
Hyrimoz (adalimumab-adaz)
Avastin 2 2
2017 Renflexis (infliximab-abda) Ogivri (trastuzumab-dkst)
Cyltezo (adalimumab-adbm) Ixifi (infliximab-qbtx) Rituxan 2 2
Mvasi (Bevacizumab-awwb)
2016 Inflectra (infliximab-dyyb) Amjevita (adalimumab-atto)
Enbrel 2 0
Erelzi (etanercept-szzs)
Epogen 1 1
2015 Zarxio (filgrastim-sndz)

Highlighted = known or believed to be marketed 24

Find more information at
www.FDA.gov/biosimilars

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 New Purple Book Database
FDA created the Purple Book, AKA the “Database of FDA-Licensed Biological Products.”
The database provides patients, payors, clinicians, and others with an accessible, easy-to-
use online search engine with more information about FDA-approved biological products,
including biosimilar and interchangeable biological products.

The searchable database utilizes features

tailored to different user needs, including:
• Main and advanced search options
• Auto-suggest search function
• Data download options
• Links to product labels
• Ability to show/hide sortable columns of
information
• Ability to print or export search results

purplebooksearch.fda.gov/

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 Resources
Visit:
• www.fda.gov/biosimilars for access to all the education materials and
information about biosimilar and interchangeable products.
• https://purplebooksearch.fda.gov/ The Purple Book: Database of
Licensed Biological Products for information on biological products,
including if products are biosimilar to a reference product.
• www.fda.gov/drugsatfda (Drugs@FDA) for information on all FDA
approved drug products, including labeling and review information.
• https://www.fda.gov/regulatory-information/search-fda-guidance-
documents for links to FDA guidance for industry
• https://www.fda.gov/advisory-committees/committees-and-meeting-
materials/human-drug-advisory-committees for drug advisory
committee meetings and materials related to biosimilars.

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