SA JOURNAL OF DIABETES & VASCULAR DISEASE
REVIEW
VOLUME 8 NUMBER 1 • MARCH 2011
19
The new world of biosimilars: what diabetologists need to
know about biosimilar insulins
IrENE KräMEr, THOMAS SAUEr
Abstract
B
iosimilar pharmaceuticals are emerging as patent
protection on the original biopharmaceutical products
expires. However, biopharmaceuticals are particularly
complex molecules, and biosimilar insulins present special
challenges. In part this reflects their structure and chemical
modification after synthesis to attain a biologically active
form. Their therapeutic window is narrow and the accuracy
of their dosing is highly dependent on the formulation and
quality of the administration device. For these reasons, the
European Medicines Agency has issued stringent guidelines
that must be fulfilled in order to receive approval as a
biosimilar soluble insulin. Prescribers should therefore
consider issues of manufacture, protein quality, formulation,
reliability of supply, and other factors that might affect
efficacy, safety and tolerability when making choices
regarding the selection of biosimilar products.
Keywords:
biosimilars, EMA, manufacturing processes,
recombinant human insulin
Introduction
Biopharmaceuticals are biological medicinal products derived
from recombinant DNA and expressed by genetically engineered
organisms to produce the target therapeutic proteins in large
quantities. The first biopharmaceutical introduced into clinical
use was recombinant human insulin (Humulin, Eli Lilly) in 1982.
Since then, hundreds of biopharmaceuticals, including cytokines,
enzymes, antihaemophilic factors and monoclonal antibodies have
received marketing authorisation in various jurisdictions.
As patents for the early biopharmaceuticals have already expired,
requests for marketing authorisation of ‘similar’ biological medicinal
products (so-called biosimilars) have been submitted in the EU, and
various biosimilars such as epoetin alfa, somatotropin and GCSF
are already available. The EMA was the first regulatory authority to
implement a regulatory framework for the marketing authorisation
of biosimilars. This requires the submission and approval of a
dossier that, while comprehensive, is less detailed than that of the
innovator product. Comparable procedures are in place in other
jurisdictions including Malaysia, Taiwan and Australia. In the USA,
the Food and Drug Administration is also preparing a regulatory
framework; products assessed by this new licensing procedure will
be referred to as follow-on biologics (FOBs).
In Europe, several human insulins are available, each with an
independent marketing authorisation based on a full dossier. The
different brands are authorised for use with specific administration
devices (generally a single-use or reusable pen). In some countries
where patent regulations are less rigorous human insulin and insulin
analogues are available that are (by definition) neither innovator
products nor biosimilars and are therefore called ‘other insulins’.
In 2007, an application to the EMA for marketing authorisation
of three biosimilar insulins was withdrawn after the CHMP issued
a provisional opinion that the products could not be approved for
human use.
1
Biosimilars are not interchangeable with originator molecules or
with each other as are traditional small-molecule generic drugs.
2
In fact, the EMA has stressed that because biosimilars and their
reference molecules are not identical, the interchange of a reference
medicine for a biosimilar medicine should be based on the opinion
of a healthcare professional.
3
Hence, it is essential for prescribers to
appreciate these issues in order to make informed choices about
the biosimilars they will encounter. This article discusses key aspects
to consider when evaluating a biosimilar, with a special focus on
biosimilar insulin.
Complexities in the manufacture of insulin
biopharmaceuticals
Protein molecules have molecular weights which may be orders of
magnitude higher than those of traditional small-molecule drugs.
Their structures are also far more complex, requiring consistency
of their primary structure (amino acid sequences), secondary
and tertiary structures (three-dimensional folding patterns), and
quaternary structure (stable association of two or more identical or
different subunits).
In the case of recombinant human insulin, the precursor protein
is synthesised by genetically modified organisms and must be
Thomas Sauer
Industrial Affairs, Chemistry and Biotechnology, sanofi-aventis Germany,
Frankfurt, Germany
Correspondence to: Prof Irene Krämer
Pharmacy Department, University Medical Center, Johannes Gutenberg-
University, Mainz, Germany.
E-mail:
S Afr J Diabetes Vasc Dis
2011;
8
: 19–25.
Abbreviations and acronyms
CHMP
Committee for Medicinal Products for Human Use
CMC
chemistry, manufacturing, controls
EMA
European Medicines Agency
EU
European Union
GCSF
granulocyte colony-stimulating factor
HCP
host-cell protein
IGF
insulin-like growth factor
NPH
neutral protamine Hagedorn
PD
pharmacodynamic
PK
pharmacokinetic
PZI
protamine zinc insulin
