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Pituitary Disorders
Figure 1: Biopharmaceuticals – A New Era of Biologics should be more similar to that used in the US, which is clearer –
‘follow-on protein product’ (FOPP), proposed by the US Food and
Drug Administration (FDA) or ‘subsequent entry biologic’ (SEB),
Biological medicines – biologics
proposed by Health Canada.
Nevertheless, Europe is the worldwide leader in the development of
a robust regulatory framework. As a consequence, pharmaceutical
• Natural biological products
• Biopharmaceuticals: In the critical year of 1985, almost 100
derived from:
biologicaly similar to natural
products, derived from:
children in clinical trials received DNA
• plants

• animal tissue
• bacteria
• human tissue
• yeast
recombinant methionyl growth hormone
• mammalian cell cultures
(rhGH), and soon after the US Food and
genetically modified by
recombinant DNA technology
Drug Administration approved rhGH
for clinical use.
Table 1: The Difference Between Generics and
Off-patent Biopharmaceuticals
development in this new area has been gaining pace since 2004. The
EU term ‘biosimilar’ medicine means that it has been compared with
Features Generics Off-patent
Biopharmaceuticals
and demonstrated that it matches the reference product in terms of
(‘Biosimilars’) quality, safety and efficacy.
Molecular weight Up to 5kDa up to 500kDa
Biopharmaceutical Growth Hormone
Production Chemical synthesis Recombinant DNA
The Reference Product
technology
The revolutionary new technology of recombinant DNA (rDNA) has
Comparability with the Bioequivalence on Bioequivalence in:
come just in time, as the supply of insulin obtained from animal
reference product: what absorption physicochemical
sources was barely sufficient to meet the demands of the rapidly
should be demonstrated? characterisation
growing global population of patients with diabetes. However, the
biological
characterisation
story of GH was more dramatic. In 1985, >25 years after the first
pre-clinical
patient had received pit-hGH, four young adult patients developed
PK/PD
Creutzfeldt-Jakob disease. All of these patients had been receiving pit-
clinical safety
hGH for many years. After intensive investigation, it became obvious
and efficacy that the pituitary glands used for the extraction of GH administered to
these patients were most probably collected from individuals with
PK = pharmacokinetics; PD = pharmacodynamics.
Creutzfeldt-Jakob disease and were contaminated with slow viruses.
2
through local regulatory authorities, but rather must follow the
centralised way laid down by the EMEA. The first production of GH with the use of genetically modified
Escherichia coli by Genentech Inc. was reported in 1977. In the
EMEA proposed the new name for off-patent biopharmaceuticals: critical year of 1985, almost 100 children in clinical trials
‘similar biological medicinal products’ or ‘biosimilars’. In the received DNA recombinant methionyl GH (rhGH),
3,4
and soon after
opinion of the author of this article, the name is misleading. There the US FDA approved rhGH for clinical use. In Europe, in 1981 Kabi
is no common understanding (and cannot be) that ‘biosimilar’ Vitrum Sweden bought the technology and after short clinical trials
carried out in Sweden,
5
the UK
6
and Germany
7
rhGH was approved
for clinical use. Kabi Pharmacia, the successor of Kabi Vitrum,
Over a period of several years and in
launched the Kabi International Growth Study (KIGS), which
corresponded to pharmacovigilance, which is now routine for newly
keeping with technology development,
developed biopharmaceuticals. The name of the study was not
the European Drug Agency developed a
changed when Kabi became Pharmacia and then Pfizer. Currently,
KIGS has been running for more than 20 years and data for more
new legislation regulatory pathway for
than 50,000 patients treated with GH have been collected in its
off-patent biopharmaceuticals.
database. It is an important source of knowledge for clinicians and
scientists.
8
Data gained provided the background for the EMEA
decision to indicate Genotropin
®
as the reference product for
describes a regulatory pathway and is a regulatory term, and it assessing clinical comparability in pre-registration studies.
does not mean that this new product is a different, yet similar,
medicine. The first approved biosimilar medicinal product was Recombinant DNA Biotechnology –
approved more than three years ago. It was the rhGH Omnitrope
®
Benefits and Hazards
and there is still a lot of misunderstanding concerning the drug The insertion of DNA encoding for the desired protein, e.g. hGH, into
among doctors and patients. To avoid confusion, the wording the host cell genome, either directly or using a plasmid as a vehicle,
48 EUROPEAN ENDOCRINOLOGY