ROBUST ANALYTICAL TESTING:
DEMONSTRATING BIOSIMILARITY
Using a Multifactorial Approach
Analytical testing is a major focus of biosimilar development.
Physicochemical studies are used to sufficiently establish
relevant product attributes such a s those that define a
product’s identity, quantity, purity, potency and consistency.
Bioactivity assays are used to evaluate how similar the
biosimilar acts like the reference product. Differences in
attributes between the proposed biosimilar and the reference
product may be compared via a fingerprint-like analysis
algorithm.12
New techniques and advancements in analytics are available.
More than one test method may be used to test a single
quality attribute. Analytical comparisons for biosimilars are
likely to be more extensive and comprehensive than those
made for reference biologics after a manufacturing change.
Analytical testing will greatly reduce the number of residual
uncertainties requiring clarification with subsequent animal
and human studies.3
design with non-inferiority or equivalence margins. If the
sponsor believes comparative testing is not required, they may
provide scientific justification in support.3
Immunogenicity: A Focus at Every Stage in the Process
The goal of immunogenicity assessment is to ascertain
potential differences between the biosimilar and the
reference product in the incidence and severity of human
immune responses.3 At least one clinical study comparing
the immunogenicity of the biosimilar and reference product
is the norm, but because immunogenicity is of concern
for any biologic product, it is evaluated at all stages of
biosimilar development.
Demonstrating Biosimilarity
Multifactorial
Approach
Human PK/PD
Studies
Comparative Clinical Immunogenicity
Evaluations
Assessment
Human PK/PD Studies
The use of comparative human PK/PD studies is fundamental
in demonstrating a high degree of similarity and is generally
expected, unless scientific evidence can be provided to show
that such studies are unnecessary. Some endpoints, including
some PD measures, may be more sensitive from those used
in the reference product’s clinical trials, and such alternative
endpoints may allow more precise comparisons of therapeutic
effects.3 One example is the use of the international
normalized ratio as a more sensitive endpoint than the
incidence of cerebral bleeding or stroke.
Comparative Clinical Evaluations
Comparative clinical evaluations are done on a case-bycase basis when they are deemed necessary, usually when
there are residual uncertainties about whether any clinically
meaningful differences exist between the biosimilar and the
reference product. If a comparative study is required, some of
the considerations that will go into the study design include
selecting a patient population and condition of use adequately
sensitive to detect any clinically meaningful differences with
the reference product, endpoints that enable precise and
meaningful comparison to the reference product and a study
Biosimilarity
When it comes to getting new biosimilar
products on the market, FDA has taken
an innovative approach to supporting
their development at every step of the
process. These... documents are designed
to help industry develop biosimilar
versions of currently approved biological
products, which can enhance competition
and may lead to better patient access
and lower cost to consumers. 15
—FDA Center for Drug
Evaluation and Research
References: 1. U.S. Food and Drug Administration (FDA). Biosimilars. March 6, 2015. FDA [website]. Available at http://www.fda.gov/Drugs/DevelopmentApprovalProcess/
HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm241720.htm. Accessed May 11, 2015. 2. Kozlowski S, Woodcock J, Midthun
K, et al. Developing the nation’s biosimilars program. N Engl J Med. 2011;365(5):385-388. 3. U.S. Food and Drug Administration (FDA). Guidance for industry: Scientific considerations
in demonstrating biosimilarity to a reference product. April 2015. 4. Sherman RE. Biosimilar biological products. Biosimilar guidance webinar. February 15, 2012. 5. U.S. Food and Drug
Administration (FDA). Guidance for industry: Scientific considerations in demonstrating biosimilarity to a reference product. February 2012. 6. U.S. Food and Drug Administration (FDA).
Guidance for industry: Quality considerations in demonstrating biosimilarity to a reference protein product. February 2012. 7. U.S. Food and Drug Administration (FDA). Guidance for
industry: Biosimilars: Questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009. February 2012. 8. U.S. Food and Drug Administration
(FDA). Guidance for Industry: Formal meetings between the FDA and biosimilar biological product sponsors or applicants. March 2013. 9. U.S. Food and Drug Administration (FDA). Guidance
for industry: Clinical pharmacology data to support a demonstration of biosimilarity to a reference product. May 2014. 10. U.S. Food and Drug Administration (FDA). Purple Book: Lists of
licensed biological products with reference product exclusivity and biosimilarity or interchangeability evaluations. April 30, 2015. FDA [website]. Available at http://www.fda.gov/Drugs/
Development ApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.
htm. Accessed May 8, 2015. 11. U.S. Food and Drug Administration (FDA). FDA approves first biosimilar product Zarxio [press release]. March 6, 2015.
FDA [website]. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm436648.htm. Accessed April 29, 2015. 12. U.S.
Food and Drug Adminstration (FDA). Guidance for industry: Quality considerations in demonstrating biosimilarity of a therapeutic protein product to
a reference product. April 2015. 13. U.S. Food and Drug Administration (FDA). Guidance for industry: Biosimilars: Questions and answers regarding
implementation of the Biologics Price Competition and Innovation Act of 2009. April 2015. 14. U.S. Food and Drug Administration (FDA). Guidance for
industry: Biosimilars: Additional questions and answers regarding implementation of the Biologics Price Competition and Innovation Act of 2009. May
2015. 15. U.S. Food and Drug Administration (FDA). Press Announcements: FDA issues draft guidance on biosimilar product development. February 9,
2012. FDA [website]. Available at http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm291232.htm. Accessed May 11, 2015.
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