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                                                      response in diabetic patients beginning insulin                                   1996;334:630-3.
Author
                                                      treatment and in patients previously treated                                   8. Bennett CL, Luminari S, et al. Pure red-cell
Professor Harald H Sitte
                                                      with other insulins. Diabetes Res Clin Pract                                      aplasia and epoetin therapy. N Engl J Med
Institute of Pharmacology
                                                      1986;2:317-24.                                                                    2004;30;351:1403-8.
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.
13a Währinger Str                                     response in patients with type 1 or type 2 dia-                                10. Bennett CL, Cournoyer D, et al. Long-term
A-1090 Vienna, Austria                                betes. Diabetes Care 2003;26:89-96.                                                 outcome of individuals with pure red cell
harald.sitte@meduniwien.ac.at                      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
References                                            treatment regimens in MS: The EVIDENCE                                              follow-up report from the Research on
1. Schellekens H. Biosimilar epoetins: How            Trial. Neurology 2002; 59(10):1496-506.                                             Adverse Drug Events and Reports (RADAR)
   similar are they? Eur J Hosp Pharm 2004;        6. McKenna RM, Oberg KE. Antibodies to                                                 Project. Blood 2005;106:3343-7.
   10(3):243-7.                                       interferon-alpha in treated cancer patients:                                   11. Killestein J, Polman C. Clinical aspects of pro-
2. Frokjaer S, Otzen DE. Protein drug stability:      incidence and significance. J Interferon                                           tein drugs. Eur J Hosp Pharm 2006; 12(6):44-5.
   a formulation challenge. Nat Rev Drug              Cytokine Res 1997;17(3):141-3.                                                 12. Belsey MJ, Harris LM, Das RR, Chertkow J.
   Discov 2005;4:298-306.                          7. Casadevall N, Dupuy E, Molho-Sabatier P,                                           Biosimilars: initial excitement gives way to
3. Di Mario U, Arduini P, Tiberti C, Lombardi G,      Tobelem G, Varet B, Mayeux P. Auto-                                                reality. Nat Rev Drug Discov 2006;5:535-6.
   Pietravalle P, Andreani D. Immunogenicity of       antibodies against erythropoietin in a patient                                 13. Sheridan C. First generic biologics finally
   biosynthetic human insulin. Humoral immune         with pure red-cell aplasia. N Engl J Med                                            approved. Nat Rev Drug Discov 2006; 5:445.




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 [1], 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
Feature
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
                                                                                            classification system.
               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 [6] 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 [2].                         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 [3]. Small distinc-      safety is not compromised. Appropriate        system [7]. 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      [8] 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
                                                                                                 Biopharmaceuticals
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-                                         paul.declerck@pharm.kuleuven.be
  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
  ing approval than currently required for     a different prescription system and join                                         1. www.who.int/medicines/services/inn/ en/
  biosimilars.                                 forces to ensure at any moment (i.e. at                                          2. EMEA guidelines on similar biological medicinal
• Different naming within the INN sys-         time of prescription, dispensation and                                              products (EMEA/CHMP/437/04).
  tem is based on a well-defined, well-        administration) the distinction between                                          3. Crommelin DJA, Jiskoot W. What makes protein
  characterisable molecular difference.        differently produced, but considered                                                drugs different? Some considerations on shifting
  Straightforward application to biosimi-      similar, biotech medicines. Regarding                                               paradigms in pharmacy… Eur J Hosp Pharm
  lars is therefore impossible since it is     the development of an alternative naming                                            2006;12(5):14-6.
  generally well recognised that subtle,       system to the INN nomenclature, it                                               4. Thorpe R, Wadhwa M, Protein therapeutics and
  but clinically important, molecular and      should be stressed that merely indicating                                           their immunogenicity. Eur J Hosp Pharm 2006;
  structural differences do exist, of          the manufacturer would be easy but not                                              12(5):17-8.
  which the detailed nature cannot be          appropriate. This would be too close to                                          5. Jiskoot W, Crommelin DJA. What makes protein
  fully determined due to a lack of sensi-     the current situation of chemical generics                                          drugs different? Pharmaceutical aspects. Eur J
  tivity of currently available methods of     and would give a false feeling of safety                                            Hosp Pharm 2006;12(5):20-1.
  analysis.                                    as a result of neglecting the possibility of                                     6. US FDA considerations on INN policies for biosi-
• 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

				
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