Update

FORUM: Policy & Regulation

Regulatory aspects of biosimilars in

Europe
Leyre Zuniga and Begona Calvo
Pharmaceutical Technology Department. Faculty of Pharmacy, University of the Basque Country, Vitoria-Gasteiz, Spain

In early 2004, the patent protection for several firstgeneration biopharmaceuticals began to expire, opening the door to the so-called biosimilars. The knowledge on biosimilars is steadily growing, and keeping
up with state-of-the-art technologies and methods for
protein characterization is compelling not only for
manufacturers but also for the authorities. The challenges now are to review current marketing approval
procedures and to develop standardised methods for
evaluating the quality, safety and efficacy of these
products.

Biosimilar products
A biosimilar drug is a medicine that is similar but not
identical to a biological medicine that has already been
authorised (the biological reference medicine) [1,2]. This
concept of a similar biological medicinal product has been
clarified by different regulatory bodies such as the EMEA
(European Agency for the Evaluation of Medicinal Products) and FDA (Food and Drug Administration), among
others.
These products do not meet the conditions for being
defined as generic medicinal products, mostly because of
differences between the similar biological medicinal product and the reference biological medicinal product in
terms of raw materials or manufacturing processes. Therefore, for a biosimilar product to be approved, the results of
appropriate pre-clinical tests or clinical trials relating to
these conditions must be provided [3].
The EMEA has laid down the following requirements for
the Marketing Authorisation Applications of a biosimilar
product:
 Comparability studies are required between the biosimilar and the chosen reference medicinal product.
 Nonclinical studies, although usually less extensive
than those for innovatory applications, will be required
for the biosimilar.
 Clinical studies will be needed to support the safety and
effectiveness of a biosimilar. In particular, the studies
must address immunogenicity concerns.
 Post-market pharmacovigilance plans will be expected
as part of approval commitments.

Corresponding author: Calvo, B. (b.calvo@ehu.es).

Marketing Authorisations for products derived from

biotechnology
A wide range of licenced biosimilars are available in several countries, including China, India and South Korea.
Examples of such marketed products include interleukins,
interferons, erythropoietins, growth factors, hormones,
enzymes and monoclonal antibodies [4]. By contrast, there
are considerably fewer biosimilars on the European market; these are mainly somatropin, epoetin and filgrastim
products. Nevertheless, Europe has already established an
advanced regulatory framework to enable the approval of
these medicines. Comparable regulatory oversight is currently under discussion in the United States, Canada and
Japan [4].
The European Directive 2001/83/EC [5], as amended by
Directive 2003/63/EC [6] and Directive 2004/27/EC [3],
defines the regulatory process for biosimilars and lays
down specific guidelines. These guidelines comprise an
overarching guideline as well as more general guidelines
concerning the product quality and other clinical and nonclinical issues. Product-specific guidelines are also available, and the EMEA is in the process of developing
additional product-specific guidelines and is planning to
update these guidelines as new information comes to light
(Table 1). In Europe, pharmaceutical products derived
from biotechnology can only be registered using the Centralised Procedure, resulting in a European Union (EU)
licence that is valid in all Member States [7].
The European system for biosimilar approval devotes
special attention to concerns over potential immunogenicity of a biosimilar and to post-marketing testing and
surveillance to detect any potential safety issues. Unfortunately, the immunogenicity of biosimilars often cannot be
fully predicted using preclinical studies, and clinical
immunogenicity studies are thus required before approval.
Therefore, safety data will be needed before Marketing
Authorisation and will also be required post marketing
It is also worth mentioning that the granting of approval
does not mean that the biosimilar product can be automatically substituted for the reference product and vice versa.
This decision should only be taken after obtaining the
opinion of a qualified health professional. Several countries,
such as France, Spain, Italy, Germany, the Netherlands, the
UK and Sweden, have established legislative measures to
prohibit the automatic substitution of these products.
Another issue regarding biosimilars is the use of the
International Non-proprietary Name (INN) [4,8]. In the

0167-7799/$ see front matter 2009 Elsevier Ltd. All rights reserved. doi:10.1016/j.tibtech.2009.03.005 Available online 19 May 2009

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Update

Trends in Biotechnology Vol.27 No.7

Table 1. European biological guidelines of relevance for biosimilarsa

Guideline reference number
Overarching guideline
CHMP/437/04

Guideline title

Date b

Similar Biological Medicinal Product

PD: Sep 2005

ED: Oct 2005

Quality issues guidelines

CPMP/BWP/3207/00

(Rev.1) Comparability of Medicinal Products Containing Biotechnology-Derived Proteins as

Active Substance: Quality Issues
Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active
CHMP/49348/05
Substance: Quality Issues
Non-clinical and clinical issues guidelines
(ICH Topic Q5E) Step 4. Note for Guidance on Biotechnological/Biological Products Subject
CPMP/ICH/5721/03
to Changes in their Manufacturing Process
Similar Biological Medicinal Products Containing Biotechnology-Derived Proteins as Active
CHMP/42832/05
Substance: Non-Clinical and Clinical Issues
Comparability of Biotechnology-Derived Medicinal Products after a Change in the
CHMP/BMWP/101695/06
Manufacturing Process: Non-Clinical and Clinical Issues
Immunogenicity Assessment of Biotechnology-Derived Therapeutic Proteins
CHMP/BMWP/14327/06
Product-specific guidelines
CHMP/31329/05

PD:
ED:
PD:
ED:

Dec 2003
Dec 2003
Feb 2006
Jun 2006

PD:
ED:
PD:
ED:
PD:
ED:
PD:
ED:

Dec 2004
Jun 2005
Feb 2006
Jun 2006
Jul 2007
Nov 2007
Jan 2008
Apr 2008

PD: Feb 2006

ED: Jun 2006

CHMP/BMWP/118264/07

Annex to Guideline on Similar Biological Medicinal Products Containing BiotechnologyDerived Proteins as Active Substance: Non-Clinical and Clinical Issues Guidance on
Biosimilar Medicinal Products Containing Recombinant Granulocyte-Colony Stimulating
Factor
Annex to Guideline on Similar Biological Medicinal Products Containing BiotechnologyDerived Proteins as Active Substance: Non-Clinical and Clinical Issues Guidance on
Similar Medicinal Products Containing Somatropin
Annex to Guideline on Similar Biological Medicinal Products Containing BiotechnologyDerived Proteins as Active Substance: Non-Clinical and Clinical Issues Guidance on
Similar Medicinal Products Containing Recombinant Human Insulin
Annex to Guideline on Similar Biological Medicinal Products Containing BiotechnologyDerived Proteins as Active Substance: Non-Clinical and Clinical Issues Guidance on
Similar Medicinal Products Containing Recombinant Erythropoietins
Similar Biological Medicinal Products Containing Low-Molecular-Weight Heparins

Draft guidelines
CHMP/BMWP/102046/06

Similar Medicinal Products Containing Recombinant Interferon a

PD: Release for

consultation Oct
2007

Development of a CPMP Guideline on Comparability of Biotechnology-Derived Products

Similar Biological Medicinal Products Containing Recombinant a-Interferon Annex to
the Guideline on Similar Biological Medicinal Products Containing Biotechnology-Derived
Proteins as Active Substance (Non) Clinical Issues
Similar Biological Medicinal Products Containing Low-Molecular-Weight Heparins:
Non-Clinical Issues

PD: Jun 1998

PD: Release for
consultation Apr
2006
PD: Release for
consultation Jan
2007
PD: Release for
consultation Jul
2008
PD: Release for
consultation Mar
2009

CHMP/94528/05

CHMP/32775/05

CHMP/94526/05

Concept papers
CPMP/BWP/1113/98
CHMP/BMWP/7241/2006

CHMP/BMWP/496286/06

EMEA/CHMP/BMWP/170734/08

Revision of the Guidance on Similar Medicinal Products Containing Recombinant

Erythropoietins

EMEA/CHMP/114720/2009

Immunogenicity Assessment of Monoclonal Antibodies Intended for In Vivo Clinical Use

PD: Feb 2006

ED: Jun 2006
PD: Feb 2006
ED: Jun 2006
PD: Mar 2006
ED: Jul 2006
PD: Apr 2009
ED: Oct 2009

http://www.emea.europa.eu/htms/human/humanguidelines/multidiscipline.htm.
PD = publication date; ED = effective date.

context of global pharmacovigilance, the INN is a useful

tool but should not be the sole means of product identification for biosimilars. All available tools should be
employed, such as lot number, manufacturer and other
relevant information (Box 1).
EMEA guidelines
The EMEA guidelines on biosimilar products consider biosimilars as similar but non-identical entities to the innovator product (chosen reference medicinal product) and stress
the importance of the manufacturing process, which conditions the characteristics of the biological medicine product. Small differences can arise in the biosimilar product
386

owing to changes in the manufacturing process. Such differences are very difficult to analyse and might have significant
impact on safety and efficacy. This is illustrated by the case
of the epoetin-a molecule Eprex1, which is used for the
treatment of pure red cell aplasia (PRCA). A small and
seemingly inconsequential change in the Eprex1 manufacturing process, namely the switch from human serum albumin in the product formulation to polysorbate 80, had a
critical impact on PRCA patients [9,10]. Thus, the safety and
efficacy profile of biosimilar products is highly dependent on
the robustness and control of quality aspects.
In Europe, for any biosimilar, the chosen reference
medicinal product must be a medicinal product authorised

Update
Box 1. Important issues related to biosimilars
 Biosimilar medicines cannot be considered biogenerics owing to,
in particular, differences relating to raw materials or differences in
manufacturing processes of the similar biological medicinal
product and the reference biological medicinal product.
 Approval of biosimilars requires the planning of comparability
studies covering quality and pre-clinical and clinical aspects
between the biosimilar and the chosen reference medicinal
product.
 Biosimilars cannot be assumed to have the same immunogenicity
profile as the original product. Because immunogenicity is largely
unpredictable, the assessment of a biosimilar must be based on (i)
a thorough riskbenefit assessment and (ii) a robust post-marketing risk management program.
 Biosimilars should not be substituted without the oversight of a
prescribing physician. Unauthorised or unrecorded substitution
must be avoided.
 The EMEAs decision to approve a biosimilar product can depend to
a certain extent on the applicants ability to convince the Agency
that suitable pharmacovigilance plans will be implemented.

in the EU, on the basis that a complete dossier is available

in accordance with the provisions of Article 8 of Directive
2001/83/EC [5], as amended. This reference product will be
used throughout the comparability program for quality,
safety and efficacy studies during the development and
approval process of a biosimilar to generate coherent data
and conclusions.
Approval will result in the publication of a European
Public Assessment Report (EPAR; http://www.emea.
europa.eu/htms/human/epar/eparintro.htm), a public summary written in collaboration with the applicant. The
EPARs objective is to improve the transparency of the
regulatory process, describing the regulatory history of the
application in detail [11].
In practice, the guidelines required before approval will
be granted will translate into increased development costs,
which are mainly associated with Phase III testing requirements, and will likely affect the pricing of the final products, potentially resulting in savings in the cost of a
biosimilar that might be less than expected compared to
that of a synthetic generic drug [1214].
Conclusion
Although the EU currently has the most advanced regulatory pathways for biosimilars, there is no harmonised worldwide regulatory system for these products. A well-defined
regulatory framework will need to be developed that can be
further expanded in response to increasing experience with,
and scientific knowledge of, biosimilars. It is important that
such a regulatory framework will not only guarantee that
biosimilars are safe, efficacious and of consistent quality but
also ensure traceability, pharmacovigilance and coherent
data collection for this new class of product.
There is still a lack of clear definition in many aspects of
biosimilar development guidelines. For example, the
EMEAs decision to approve a biosimilar product can depend

Trends in Biotechnology

Vol.27 No.7

to a certain extent on the applicants ability to convince the

Agency that suitable pharmacovigilance plans will be implemented. However, the criteria of what constitutes an acceptable pharmacovigilance plan remain to be determined.
Another crucial step in the regulatory procedures for
biosimilars is to set up the requirements for non-clinical
and clinical data that are necessary and sufficient to
demonstrate biosimilarity.
For these reasons, it is recommended that any applicant
seeks scientific advice from the Agency as early as possible
during the development stages to ensure that the company
is following the right strategy, which will save time and
money.
References
1 European Medicines Agency (2007) Questions and answers on
biosimilar medicines (similar biological medicinal products). Doc.
Ref. EMEA/74562/2006 (http://www.emea.europa.eu/pdfs/human/
pcwp/7456206en.pdf)
2 Mellstedt, H. et al. (2008) The challenge of biosimilars. Ann. Oncol. 19,
411419
3 The European Parliament and the Council of the European Union (2004)
Directive 2004/27/EC of the European Parliament and of the Council of
31 March 2004 amending Directive 2001/83/EC on the Community code
relating to medicinal products for human use. In Official Journal of the
European Union, L136, pp. 3457 (http://eur-lex.europa.eu/LexUriServ/
LexUriServ.do?uri=OJ:L:2004:136:0034:0057:EN:PDF)
4 Joung, J. et al. (2008) WHO informal consultation on regulatory
evaluation of therapeutic biological medicinal products held at WHO
Headquarters, Geneva, April 2007. Biologicals 36, 269276
5 The European Parliament and the Council of the European Union
(2001) Directive 2001/83/EC of the European Parliament and of the
Council of 6 November 2001 on the Community code relating to
medicinal products for human use. In Official Journal of the
European Union, L311, pp. 67128 (http://eur-lex.europa.eu/
LexUriServ/LexUriServ.do?uri=OJ:L:2001:311:0067:0128:EN:PDF)
6 The Commission of the European Communities (2003) Commission
Directive 2003/63/EC of 25 June 2003 amending Directive 2001/83/EC
of the European Parliament and of the Council on the Community code
relating to medicinal products for human use. In Official Journal of the
European Union, L159, pp. 4694 (http://eur-lex.europa.eu/
LexUriServ/LexUriServ.do?uri=OJ:L:2003:159:0046:0094:EN:PDF)
7 European Commission (2006) Chapter 4. Centralised procedure. Volume
2A Procedures for Marketing Authorization. In The Rules
Governing Medicinal Products in the European Union, European
Commission (http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/
vol-2/a/chap4rev200604%20.pdf)
8 Boring, D. (1997) The development and adoption of non-proprietary,
established, and proprietary names for pharmaceuticals. Drug Inf. J.
31, 621634
9 Rossert, J. (2005) Erythropoietin-induced, antibody-mediated pure red
cell aplasia. Eur. J. Clin. Invest. 35 (Suppl. 3), 9599
10 Boven, K. et al. (2005) Epoetin-associated pure red cell aplasia in
patients with chronic kidney disease: solving the mystery. Nephrol.
Dial. Transplant. 20 (Suppl. 3), iii33iii40
11 Fruijtier, A. (2006) Registration procedures for medicinal products:
past, present and future. Update of chapter 11. In Fundamentals of EU
Regulatory Affairs (Michor, S. and Rowland, K., eds), pp. 125136,
Regulatory Affairs Professionals Society
12 Covic, A. and Kuhlmann, M.K. (2007) Biosimilars: recent
developments. Int. Urol. Nephrol. 39, 261266
13 Gottlieb, S. (2008) Biosimilars: policy, clinical, and regulatory
considerations. Am. J. Health Syst. Pharm. 65, S2S8
14 Moran, N. (2008) Fractured European market undermines biosimilar
launches. Nat. Biotechnol. 26, 56

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