REVIEW
SA JOURNAL OF DIABETES & VASCULAR DISEASE
24
VOLUME 8 NUMBER 1 • MARCH 2011
With regard to quality, suppliers should be asked for a written
statement that covers aspects such as the purity of the biosimilar
protein, the upper limits for impurities such as aggregates or
endotoxins, differences in isomer pattern, and clinical consequences
of any potential differences. In the case of insulin impurities such
as desamido forms may arise as by-products of conversion from
proinsulin to insulin by removal of the C-peptide and regeneration
of the three-dimensional form of the molecule.
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Moreover, with
regard to formulation, any differences between the biosimilar
and the originator molecule plus choice of excipients, stabilisers
and preservatives should be provided, Additionally administration
(either device or technique) should be explicit. If the biosimilar is
administered by a different method from the originator product,
e.g. with a new device, teaching materials should be available to
train patients and caregivers to use the different system. It is also
important to know the product’s shelf life and its susceptibility to
degradation if it is stored improperly (for example, if accidentally
stored at room temperature instead of being refrigerated).
Quality control toensurebatch-to-batch consistency is paramount
with insulin preparations. There should be a guaranteed stock
position which will maintain supplies if a newly produced batch
fails to meet all the required standards of quality. A sustainable
supply chain with reliable transportation conditions should also be
established.
Particular attention should be given to any differences in clinical
activity, biological activity per unit, relative biological potency and
dosage of a biosimilar compared with the originator molecule. The
known safety and tolerability profile of the biosimilar, as well as
precautions or contraindications for its use, should be comparable
with the originator molecule. Because clinical trials which enrol
relatively small numbers of patients cannot identify rare side-
effects, it is obligatory to monitor safety during the post-approval
phase. The use of more than one biosimilar product (for example,
a biosimilar insulin and a biosimilar epoetin for the diabetic patient
with renal failure) may present an additional layer of complexity
regarding safety issues. Similarly, substituting one insulin for
another may require dose adjustment. While the development of
antibodies to insulin rarely has major clinical consequences, it may
have an impact on efficacy (because higher insulin doses may be
necessary) and tolerability (mainly in the form of local injection site
reactions). Hence, a biosimilar product should receive thorough
antibody tests extending into the post-marketing period.
Summary and conclusions
Biosimilar products such as epoetin alfa biosimilars are already
marketed in the EU, and biosimilar insulins are expected shortly.
Patients with diabetes are often candidates to receive both types
of products. Therefore, it is imperative for prescribers to be aware
of issues presented by biosimilar products, and particularly the
special challenges presented by biosimilar insulin. Biosimilars
are not interchangeable with the corresponding originator
biopharmaceuticals in the same way that non-peptide, small-
molecule generic molecules are interchangeable with the original
products. Any apparently minor modification in the manufacturing
or formulation of a product such as insulin, or in the administration
device, has the potential to cause untoward clinical consequences,
even if the product appears to be physicochemically equivalent to
an accepted reference standard. The consequences are particularly
relevant for insulin as the therapeutic window is narrow. For this
reason, the EMA has developed robust regulatory requirements
before marketing authorisation can be granted for a biosimilar
insulin. Prescribers should consider critical issues regarding the
manufacture, protein quality and formulation, supply, clinical
efficacy, safety and tolerability of biosimilar insulins before
substitutin
Table 1.
A checklist of issues to consider when selecting a biosimilar
insulin product.
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Manufacturer
• Reputation, reliability, experience with biopharmaceuticals
• Location of manufacture of the medicinal product
• Location of the manufacture of the active drug substance (are third
parties involved?)
• Dissemination of safety updates and changes in manufacturing process
Protein quality and formulation
• Bioassays: appropriateness, comparisons with reference product
• Levels of foreign proteins, DNA, pyrogens, endotoxins, aggregates
• Formulation: choice of excipients, stabilisers and preservatives
• Administration device or technique; teaching materials for use of a
different administration system
• Shelf life, susceptibility to degradation
• Consistency between batches; appropriate quality controls
Reliability of supply
• Stock position
Clinical efficacy
• Clinical trials carried out with different batches of the biosimilar product
itself: adequacy of design, results, consistency and generalisability of
results
Clinical safety and tolerability
• Comparison of safety and tolerability profile with reference product
• Precautions or contraindications for use of the biosimilar
• Serious adverse events
• Immunogenicity (especially as compared to reference product); selection
of antibody tests
• Post-marketing risk management programmes: required laboratory tests,
antibody testing, pharmacovigilance programmes to detect infrequent
adverse events
Key messages
•
Unlike non-peptide small-molecule generics, biosimilars are
not identical to the originator
• Biosimilar insulins are challenging because insulin has a
complex structure and a narrow therapeutic window
• The dosing accuracy of biosimilar insulins depends on the
quality of the administration device
• regarding biosimilars, consider the manufacturer, protein
quality, formulation, reliability of supply, clinical efficacy,
safety and tolerability
