What is a biosimilar?
In March 2015, the U.S.
Food and Drug Administration (FDA) approved the first biosimilar in the United
States. Since then, FDA biosimilar approvals have slowly increased over the
years: 3 in 2016; 5 in 2017; 7 in 2018; and 7 through July 2019.
A biosimilar is a biological product that is highly similar to
the reference product notwithstanding minor differences in clinically inactive
components and that has no clinically meaningful differences in terms of
safety, purity, or potency from an existing FDA-approved reference product.1
·
To ensure that a
biosimilar is highly similar, state-of-the-art technology is used
to compare characteristics of the products, such as purity, chemical identity,
and bioactivity. The biosimilar manufacturer uses results from these
comparative tests, along with other information, to demonstrate that the
biosimilar is highly similar to the reference product2 (see
Table 1)
o
Minor differences in
clinically inactive components are acceptable, as well as minor within-product
lot-to-lot variability inherent during the manufacturing process of any
biologic, be it a biosimilar or a reference product
·
To demonstrate
that no clinically meaningful difference exists in safety and efficacy,
human pharmacokinetics and pharmacodynamics studies must be conducted, along
with an assessment of clinical immunogenicity, and, if needed, additional
clinical studies2
Table 1: Parameters Evaluated When Characterizing
Biosimilars and Reference Products3 |
·
Aggregation ·
Amino acid sequence ·
Degradation profile for stability ·
Functional properties (bioassays, binding, enzyme
kinetics) ·
Molecular weight ·
Heterogeneity ·
High order structure ·
Impurity profile ·
Posttranslational modifications ·
Secondary, tertiary, and quaternary structure |
Biosimilars versus
generics
While the concept of
generics and biosimilars may seem comparable, and both are approved via
abbreviated approval pathways, these two alternatives to brand-name medications
differ greatly:
Due to the highly technical process of developing large biologic
molecules (see Figure 1), biosimilars are not required to be
identical, but must be proved to be highly similar to the
reference product.2,4
·
Generic medicines are small molecules that use
the identical active ingredient, and must demonstrate bioequivalence to
the reference product2,4
o
Bioequivalence
suggests that the generic drug has similar pharmacokinetic parameters, such as
area under the curve (AUC), peak concentration (Cmax), time to peak
concentration (Tmax), and absorption lag time (tlag), to
the reference agent
Biosimilar development
and approval processes
While biosimilars are
licensed (approved) by the FDA under section 351(k) of the Public Health
Service Act (PHS Act) enacted in 1944, the Biologics Price Competition and
Innovation Act, via the Affordable Care Act of 2010, created an abbreviated
licensure pathway for biosimilar products under the PHS Act.5
There are currently 600 biosimilar trials being conducted, with
at least 146 unique molecules.5 Biosimilars trials are
primarily focused on oncology therapy, with a 36% share, and immunology
treatment comprises 21% of the pipeline, which means that these two segments
account for more than half of the total trials.
The abbreviated approval pathway for biosimilars focuses on
different aspects of the regulatory pathway (see Figure 2).6
·
Unlike reference
originator biologics, which direct most of their efforts in clinical studies to
assess dosing, efficacy, and safety, the biosimilar approval process centers
around characterization as the foundation of the development program
·
Animal studies
(nonclinical) can aid in assessing toxicity, resolve any uncertainties
remaining after the characterization, and include pharmacokinetics and
pharmacodynamics studies
·
Pharmacokinetics,
pharmacodynamics, and immunogenicity studies are also required in healthy
people
·
Finally, comparative
trials with a population diagnosed with an approved indicated disease must
demonstrate clinical efficacy and safety that shows no clinically meaningful
differences
Biosimilar dispensing
Unlike the typical generic agents dispensed at a pharmacy for
self-administration, current FDA-approved biosimilars require infusions. These
infusions usually take place at a hospital, doctor’s office, or independent
infusion center, and on occasion at a patient’s home, via home health services.
Extrapolation
The basis of biosimilar development approval for a condition is
the demonstration of highly similar chemical and biological parameters to the
reference product, not on efficacy. Therefore, unlike reference products, where
expanding a drug’s indications requires years of testing in target disease
population, testing of biosimilars can be conducted in one disease
population, and if approved, results can be “extrapolated”, and based on indications
of the reference drug.3,7,8
Are long-available
reference products “biosimilars” of their approved versions?9-11
By nature, highly complex biologic agents, produced by living
cells and developed through an intricate, multistep manufacturing process, are
more sensitive to changes in any step of the manufacturing process (see Figure
3).
·
Manufacturing
evolution: Known changes in
the manufacturing process can lead to changes in a biologic’s attributes, and
some could shift outside of established acceptable ranges. It is not uncommon
for reference biologics to go through a number of manufacturing process
changes, with some undergoing over 20 changes since FDA approval. Although in
some cases regulators may require new clinical trials after such process
changes are made, they are more likely to request recharacterization of the
molecule, and often will rely on surveillance efforts to identify important
clinical or safety signals
·
Manufacturing
drift: Unintended or
unexplained changes in manufacturing processes can also occur and may
lead to deviations in product attributes, which can result in a shift in
quality
·
Manufacturing
divergence: Varying types of
manufacturing changes may occur across facilities (different regions or
countries), producing deviant forms of the same biologic
Thus, it is important to recognize that over time these changes
in the reference biologic manufacturing process are essentially producing
“biosimilars” of the originally approved product.
References
1.
Biosimilars
action plan: balancing innovation and competition. U. S. Food & Drug
Administration website. https://www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/UCM613761.pdf.
Updated July 2018. Accessed July 25, 2018.
2.
Biosimilars.
U.S. Food & Drug Administration website. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/default.htm.
Updated November 14, 2017. Accessed February 16, 2018.
3.
Gerrard
TL, Johnston G, Gaugh DR. Biosimilars: extrapolation of clinical use to other
indications. GaBI J. 2015;4:118-124.
4.
Camacho
LH, Frost CP, Abella E, Morrow PK, Whittaker S. Biosimilars 101: considerations
for U.S. oncologists in clinical practice. Cancer Med.
2014;3:889-899.
5.
Purple
Book: lists of licensed biological products with reference product exclusivity
and biosimilarity or interchangeability evaluations. U.S. Food & Drug
Administration website. https://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/TherapeuticBiologicApplications/Biosimilars/ucm411418.htm.
Updated February 2, 2018. Accessed February 16, 2018.
6.
Olech
E. Biosimilars: rationale and current regulatory landscape. Semin
Arthritis Rheum. 2016;45:S1-S10.
7.
Tesser
JRP, Furst DE, Jacobs R. Biosimilars and the extrapolation of indications for
inflammatory conditions. Biologics. 2017;11:5-11.
8.
Weise
M, Kurki P, Wolff-Holz E, Bielsky MC, Schneider CK. Biosimilars: the science of
extrapolation. Blood. 2014;124:3191-3196.
9.
Ramanan
S, Grampp G. Drift, evolution, and divergence in biologics and biosimilars
manufacturing. BioDrugs. 2014;28(4):363-372.
10. Mehr SR, Zimmerman MP. Is
a biologic produced 15 years ago a biosimilar of itself today? Am
Health Drug Benefits. 2016;9(9):515–518.
11. Schneider CK. Biosimilars
in rheumatology: the wind of change. Ann Rheum Dis.
2013;72(3):315-318.
https://sagentbiosimilars.com/learning-about-biosimilars/
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