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Professor Harald H Sitte
with other insulins. Diabetes Res Clin Pract aplasia and epoetin therapy. N Engl J Med
Institute of Pharmacology
Center for Molecular Medicine and 4. Fineberg SE, Huang J, Brunelle R, Gulliya KS, 9. Schellekens H, Jiskoot W. Eprex-associated
Pharmacology Anderson JH, Jr. Effect of long-term exposure pure red cell aplasia and leachates. Nat
Medical University Vienna to insulin lispro on the induction of antibody Biotechnol. 2006;24:613-4.
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A-1090 Vienna, Austria betes. Diabetes Care 2003;26:89-96. outcome of individuals with pure red cell
firstname.lastname@example.org 5. Panitch H, Goodin DS et al. Randomised, aplasia and antierythropoietin antibodies in
comparative study of interferon beta-1a patients treated with recombinant epoetin: a
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BIOLOGICALS IN THE ERA OF BIOSIMILARS:
IMPLICATIONS FOR NAMING AND PRESCRIBING
Professor Paul Declerck, PhD
In this article the debate surrounding the naming system for biosimilars and its impact on future
prescribing practice are discussed.
Introduction The INN system - developed cally referred to by a chemical name
Unlike generics of chemical drugs, with chemically-derived (or formula)” – thus generic ‘chemical’
biosimilars are similar but not identical molecules in mind substances will have the same INN as
to the original product. Therefore, and in The current International Non-proprie- the original active substance.
relation to their safe use and pharmaco- tary Name (IN) system , introduced in
vigilance, questions are being raised 1950 and administered by the World Application of the INN system implies
about the (im)possibility of applying the Health Organization (WHO), lays down that analytical tools are available to
current INN system for adequate naming guidelines for the universally available, prove unambiguously that two products,
of biotherapeutics in general and biosim- unique naming of pharmaceutically from two different manufacturers and/or
ilars in particular. Should biosimilars active substances. Such an international produced by different processes, having
have distinct INNs or should a new inde- nomenclature is essential to precisely the same INN, are identical and their
pendent naming system be developed? identify each substance and ensure the effect on the patient will be the same.
What measures should be taken to safe prescription and dispensation of Subsequently the INN provides the
ensure that healthcare professionals medicines. It should be realised that the healthcare community with a common
realise that biosimilars should not be INN system was designed to identify language on pharmaceutical substances.
merely considered as copies, and thus chemically-derived (small molecule)
that the patient may react differently medicines at a time before biotechnology Biosimilars: challenging the
upon substitution? Does the approach of existed. In this respect, INNs are select- INN system
naming have an impact on prescribing ed in principle “only for single, well- Scientific breakthroughs in healthcare
practices? defined substances that can be unequivo- biotechnology have revolutionised treat-
• Volume 13 • 2007/1 EJHP is the Official Journal of the European Association of Hospital Pharmacists (EAHP) www.ejhp.eu 51
ments in the past 25 years. Cloning of unsafe; they are subject to an approval The doctor must ensure that the biotech
human genetic material and the develop- process which requires substantial addi- medicine prescribed is carefully chosen,
ment of in vitro biological production tional data to that required for chemical and the pharmacist must ensure that the
systems has allowed the production of generics, although not as comprehensive prescription is dispensed precisely.
virtually any recombinant DNA-based as for the original biotech medicine. There is little, if any, room for substitu-
biological substance for the eventual However, the safe application of biologics tion, and this must be clearly understood
development of a drug. Monoclonal anti- is also dependent on an informed and by the medical community. Without sig-
body technology combined with rDNA appropriate use by healthcare profession- nificant education and discipline among
technology has paved the way for tailor- als. Doctors and pharmacists must know medical practitioners, inadvertent substi-
made and targeted medicines. Gene- and if and when changes happen in the tution could harm human health, while at
cell-based therapies are emerging as new system, so they can effectively manage the same time making it impossible to
approaches. patient safety. The current INN system, trace which medicine caused the reac-
tion. As we move into a time of person-
alised medicine, identification and trace-
There is little, if any, room for substitution, ability become increasingly important
and this must be clearly understood by and require a stronger and more robust
the medical community.
Is it time for a rethink of the INN system?
Or is it more appropriate to develop an
Since the expiry of the patent of the first whereby drugs with the same active independent naming system for biological
approved biotech drug, ‘copying’ and ingredient (irrespective of their produc- and biotechnological substances? This is
marketing of these biological substances tion process) are given the same name, certainly an issue for debate within the
(biosimilars) can be offered by any other could easily lead to inadvertent substitu- international medical and pharmaceu-
biotech company and might possibly, as tion. Irrespective of the decisions made tical community, through the appropriate
with generics, reduce the cost to patients on the system nomenclature, hospital authorities such as the European Medicines
and social security systems. pharmacists will undoubtedly play an Agency (EMEA), the US Food and Drug
important role in the safe use of biosimi- Administration (FDA) and the WHO.
Each biotech medicine is made in a lars. In this respect also the education of Recently the FDA presented a position
living cell. Because no two cell lines, other healthcare professionals by hospital paper  saying that there is no need for
developed independently, can be consid- pharmacists seems to be an obvious step. modifying the INN system for the appropri-
ered identical, biotech medicines cannot ate naming of biosimilars. Their view is
be fully copied. This is recognised by the Responding to the challenge: a mainly based on the fact that, in the US
European regulatory authorities and has matter of adequate naming and alternative mechanisms exist for preventing
resulted in the establishment of the term prescription practices inappropriate substitution even if two prod-
“biosimilar” in recognition of the fact How can the healthcare community ucts have the same INN. The FDA also
that, whilst biosimilar products are simi- respond appropriately to this new chal- points out that product interchangeability
lar to the original product, they are not lenge? The INN system remains a cor- decisions are beyond the scope of the
exactly the same . nerstone of chemical pharmaceutical WHO’s INN experts. The European
identification, and provides clarity for Generic medicines Association also plead-
Indeed, biotech medicines are much more the healthcare community so that patient ed for not changing the INN based naming
complex in structure . Small distinc- safety is not compromised. Appropriate system . They argue that demonstration
tions in the cell line, the manufacturing conventions to provide separate names of comparability between two biologicals is
process or the surrounding environment for biotech medicines would be one pos- sufficient to allow the same INN. On the
can make a major difference in side sibility to help avoid inadvertent substi- other hand in a joint position paper the
effects observed during treatment, i.e. two tution by pharmacists and compromises European Biopharmaceutical Enterprises
similar biologics can trigger very differ- in patient safety or pharmacovigilance. and the European Federation of
ent immunogenic responses in patients [4, Pharmaceutical Industries and Associations
5]. Therefore, and unlike chemical phar- The onus of responsibility of healthcare  stated that either distinct brand naming
maceuticals, substitution between biolog- professionals cannot be underestimated. or, in view of current prescribing practices
ics, including biosimilars, can have clini- At the very least, doctors must ensure in Europe, distinct INN naming is a prereq-
cal consequences and do create health that the specific biotech medicine (origi- uisite for guaranteeing traceability and ade-
concerns for patients. nator or any biosimilar) prescribed in the quate pharmacovigilance. The WHO has
first instance is taken throughout the not yet presented their position on biosimi-
This does not mean that biosimilars are course of the treatment with each patient. lar INNs.
52 • Volume 13 • 2007/1 www.ejhp.eu
At a first glance the most sensible course analytical methods, affect the clinical nator or biosimilar) a distinct brand
of action would appear to be the assign- (side) effects of the drug. naming, together with an adapted SPC,
ment of distinct INNs to biosimilars. It should be a prerequisite for granting a
should be realised, however, that the Until the possible development of a scien- marketing authorisation for each
INN system was originally developed to tifically solid, clear, unambiguous differ- biosimilar. Obviously, automatic sub-
be applied to chemical, well-defined, ential naming system it appears that the stitution and active substance based
substances and has also adopted a specif- following actions may be the first to be prescription should be banned for bio-
ic system for particular groups of taken: logics. It is realised however that these
biological compounds associated with • obligation to assign different brand suggested requirements may interfere
their physiological action. The latter is names explicitly not suggestive towards with current legislation. In particular
restricted to the use of common prefixes the originator or towards other biosimi- the differences observed between the
(e.g. “som-“ for growth hormones) or lars containing the same active sub- different member states in Europe may
suffixes (e.g. “-relin” for hormone release stance complicate the proposed approach.
stimulating factors or “-cog” for blood • explicit warning in the summary of Therefore the EMEA and the con-
coagulation factors). However, none of product characteristics (SPC) and cerned European legal authorities
the current INN rules is applicable to patient information leaflet that, because should sit together with the national
solve the naming problem of biosimilars. of different production and formulation medicines agencies to prevent the legal
Moreover a number of elements may processes, the active substance of one hurdles from compromising patient
point towards the “inappropriateness” of brand should not be considered identical safety. In the mean time the search for
different INN names: to the active substance of another brand a long term adequate solution regarding
• The introduction of the first biotech • unlike chemically derived substances, the design of a new (INN independent)
produced active substances as a prescription of biologics based on active naming system for biosimilars should be
‘replacement’ for plasma-derived or substance name should be prohibited for started as soon as possible.
tissue-derived human proteins has biologics
never raised the question of different • a routine application of, for example,
INN naming even though the difference, barcode related systems of traceability. Author
and associated problems, between the Professor Paul Declerck, PhD
recombinant version and the plasma- For the benefit of the patients, the med- Laboratory for Pharmaceutical Biology
derived version is comparable to that ical community and the marketing of Katholieke Universiteit Leuven
observed today between the originator biosimilars it is strongly encouraged that Campus Gasthuisberg O&N 2, PB 824
and the biosimilars and between both biosimilar and originator compa- 49 Herestraat
biosimilars. It should be noted, however, nies recognise the potential differences B-3000 Leuven, Belgium
that the introduction of the first biotech between similar biologicals and the sub- email@example.com
drug required a much more extensive sequent hazards. Both should recognise
comparability exercise prior to market- the need for either a different naming or References
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characterisable molecular difference. differently produced, but considered drugs different? Some considerations on shifting
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• The introduction of (slight) changes in clinically relevant differences. milars, 1 September 2006, www.fda.gov/cder/
the production process, drug formula- news/biosimilars.htm
tion or manufacturing process has Conclusion 7. www.egagenerics.com/pr-2006-05-18.htm
never led to new names even though it Taken together, to keep up with current 8. www.ebebiopharma.org/topics/biosimilars/
is known that such changes might, rigorous standards concerning patient downloads/biosims_ebeefpiaposition_naming_
beyond the detection limits of current safety and the use of biologics (origi- 7july2006.pdf
• Volume 13 • 2007/1 EJHP is the Official Journal of the European Association of Hospital Pharmacists (EAHP) www.ejhp.eu 53