Over recent decades,
some of the most important therapeutic advances have involved the use of biologic
drugs. These are typically large complex molecules derived from a biological
source, such as yeast or cell culture, rather than a chemical source. Examples
of biologic drugs include monoclonal antibodies like infliximab and ipilimumab,
and smaller proteins such as insulin and erythropoietin.
Patents on many
originator biologic drugs are coming to an end allowing other companies to
produce them. This is likely to cause significant price reductions in much the
same way as generic manufacturers reduce the cost of small-molecule drugs.
However, because of the complexity of biologic drugs, the traditional
understanding of bioequivalence* with generic drugs cannot be directly applied.1
For this reason, off‑patent biologic drugs produced by alternative manufacturers
are referred to as biosimilars or ‘similar biological medicinal products’
rather than generic medicines. They are subject to different regulatory
considerations2 compared to generic small-molecule drugs because their
complexity and the way they are produced has the potential to result in
variability in the final product between manufacturers and batches.
One of the most significant safety
concerns with biosimilars is the potential risk of immune-based adverse
reactions. Because of their molecular size, biologics can directly induce
anti-drug antibodies which may have significant consequences for both safety
and efficacy. This was highlighted by experience with erythropoietin over a
decade ago when changes in manufacturing appeared to make the product more
immunogenic. This significantly increased the risk of treatment-induced pure
red cell aplasia and resulted in high fatality rates and rendered other
patients dependent on blood transfusions.3 More recently, Thailand experienced
a significant number of cases of pure red cell aplasia following the
introduction of ‘bio-copy’ erythropoietin products.4 At the time in Thailand,
these products were assessed using the same regulatory framework as for generic
small-molecule drugs, which focuses on showing bioequivalence. This is
drastically different from the current regulatory
pathways for biosimilar drugs in Australia (and internationally) which demand
clinical data showing that the biosimilar is equally as safe and efficacious as
the originator biologic drug.
While the biosimilar
regulatory framework attempts to address the concerns related to
immunogenicity, potential uncertainty remains. In a recent clinical trial of a
biosimilar etanercept, the incidence of patients with anti-drug antibodies was
lower with the biosimilar (0.7%) than with the reference drug (13.1%).5 The
significance of this finding has been debated, particularly the transient
nature and limited duration of anti-drug antibody positivity observed in these
patients. This example highlights the complexities in this area including the
technical challenges associated with detecting and quantifying anti-drug
antibodies, the timing of patient assessments compared to the original studies
of the reference product, and the assessment of the clinical impact of
anti-drug antibodies.
In an attempt to balance
the safety concerns of biosimilars against an overly onerous and costly
clinical development pathway, clinical data are not required for approval of
every potential indication.2 Registration of the biosimilar for some
indications might be based on clinical evidence of comparable clinical efficacy
and safety in another indication. This potentially increases the uncertainty of
the comparability of the biosimilar with the reference product.
It is possible that
there are differences between conditions on the basis of the indication or the
molecule. For example, the use of concurrent drugs such as an immunosuppressant
often varies between indications, with the potential for differences in the
risk of the formation of anti-drug antibodies. Likewise, the drug’s mechanism
of action may differ depending on the indication and it is possible that small
differences in physicochemical characteristics could result in differences in
clinical outcomes.
The
extrapolation of indication has been recently illustrated with the approval of
a biosimilar infliximab for inflammatory bowel disease following initial
studies conducted in rheumatoid arthritis and ankylosing spondylitis. Although
this creates a degree of uncertainty, surveys of gastroenterologists suggest
that initial reservations subsided once they gained experience with the
biosimilar.6,7 Current data suggest that the biosimilar infliximab is generally
well tolerated and efficacious in inflammatory bowel disease in patients who
have not previously received biological therapy.8,9
While clinical trials
may show comparable safety and efficacy, the trial design may not look at
switching between the reference product and the biosimilar. Open-label
extension studies of phase III trials with the biosimilar infliximab, and the
NOR-SWITCH study, a double-blind study assessing the safety and efficacy from
originator to biosimilar infliximab, are providing reassuring data of the
outcomes associated with switching therapy.8,10,11 However, data relating to
switching generally remain limited.
Administration
of biologics is more complex than with small-molecule drugs. Switching or
substituting a bioequivalent oral generic drug is often simple and may only
require patient education about the difference in its appearance. However,
because biologics are administered parentally, devices are required. Device
design is proprietary so biosimilars will have a different device not only in
appearance but also potentially in function. This could cause problems with
safety. For instance with biosimilar insulin, many patients use pen devices but
not all pens are compatible with the cartridges produced by the different
biosimilar manufacturers. Although manageable through education, care needs to
be taken to ensure that patients switching between products do not become
confused.
Because of the
uncertainties associated with the use of biosimilars, pharmacovigilance is
important. Fundamental to this is accurate documentation and reporting of the
specific products for each patient. At present naming conventions for
biosimilars are still being established. Traceability may prove difficult in
patients who undergo multiple switches or substitutions between the reference
product and the biosimilar.12
In comparison with
traditional small-molecule drugs, biosimilars have unique safety
considerations. Owing to the diversity in their structural complexity and
indications, safety will need to be considered on a drug-by-drug basis. Early
experience indicates that once biosimilars become available, initial safety
concerns will decrease. However, there remains a need for appropriate
pharmacovigilance which considers the unique properties of these drugs.
Ross
McKinnon and Michael Ward have both provided educational presentations
sponsored by AbbVie and Sanofi Aventis. Ross McKinnon has participated in
Advisory Board activities for AbbVie.
*Bioequivalence is shown when, after administration, two products produce such similar plasma concentrations of the active ingredient that their clinical effects can be expected to be essentially the same.