“Key issues on Biosimilars Guidelines development and current revision trends” Provides an overview of the guidelines and norms set forth by the European Medicines Agency (EMA) for biotherapeutics & biosimilars

1. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 11Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 11
Key issues on Biosimilars
Guidelines development and
current revision trends

2. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 22Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 22
Carlo Pini
(carlo.pini@iss.it)
Director
National Center for Immunobiologicals Research and
Evaluation - CRIVIB
Istituto Superiore di Sanità
Roma
Italian Delegate - Biologics Working Party (CHMP/BWP)
EMA - London

3. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 33Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 33
Disclaimer
• The content of the following presentation represents
the speaker’s view and does not reflect any official
point of view.
• According to the EMA policy (0044 MA/513078/2010)
– No direct conflict of interest
– One indirect conflict of interest

4. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 44Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 44
Biologicals/biotechnologicals and
biosimilarity
• Biologicals/biotechnologicals products are
complex molecules which cannot be fully
characterised from the analytical point of view
but whose quality attributes are also largely
defined by the manufacturing process.
• Therefore the “generics” concept, which is
well used for chemical entities, is not
applicable and the term “Biosimilar” has been
created

5. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 55Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 55
Biosimilar products in Europe
• Article 10 (4) of Directive 2001/83 as amended by
2004/27.
Where a biological medicinal product which is similar to a
reference biological product does not meet the conditions
in the definition of generic medicinal products, owing to,
in particular, differences relating to raw materials or
differences in manufacturing processes of the biological
medicinal product and the reference biological medicinal
product, the results of appropriate pre-clinical tests or
clinical trials relating to these conditions must be
provided. The type and quantity of supplementary data to
be provided must comply with the relevant criteria stated
in the Annex and the related detailed guidelines. The
results of other tests and trials from the reference
medicinal product's dossier shall not be provided.

6. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 66Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 66
Biosimilar products
• To support the biosimilarity approach, the biosimilar product
should be fully and extensively compared with the originator
at the quality level, but also at the non clinical and clinical level.
The size of the data to be provided is linked to the degree of
similarity which has been demonstrated at the quality level.
• This comparative approach (comparability exercise) should
take place during the first step of the development of the
biosimilar product, in order to avoid, in case of lack of
comparability at the quality level, unnecessary experiments in
animals (nonclinical) or not appropriate clinical trials

7. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 77Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 77
Comparability exercise concept and application to
biosimilarity
• The comparability exercise concept was originally
developed to evaluate the impact of changes
introduced at the production process level within
a single manufacturer.
• It is based on a comparative analysis which is
carried out at the level of DS and/or DP using
“state of the art” suitable analytical approaches
• The same approach is followed but the
comparability exercise involves the biosimilar vs
the originator.

8. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 88Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 88
European Medicines Agency (EMA) Approach
• Biosimilars are evaluated according to the centralised
procedure at EMA (2001/83)
• Documents (Guidelines and Concept Paper) have been
prepared
– General, defining the overall policy for biosimilars
– Module -specific, dealing with specific biosimilarity aspects on
quality, non clinical e clinical section
– Product-specific
• Erythropoietin, Growth hormones , G-CSF, insulin, interferon α, others.
– Issue (i.e. immunogenicity) - specific
• Quality is assessed at the CHMP/BWP level
• An ad hoc (BMWP) group was created for clinical aspects
• Final decision taken by the CHMP

9. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 99Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 99
Main Guidelines
• Guideline on similar biological medicinal products
(CHMP/437/04)
• Guideline on similar biological medicinal products containing
biotechnology-derived proteins as active substance: quality
issues (CHMP/BWP/49348/2005)
• Guideline on similar biological medicinal products containing
Biotechnology-derived proteins as active substance: Non-
clinical and clinical issues (CHMP/BMWP/42832/2005)
• Guideline on immunogenicity assessment of Therapeutic
proteins (CHMP/BMWP/14327/06)
• Product-specific Non clinical and clinical Guidelines

10. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1010Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1010
Guideline on similar biological
medicinal products (CHMP/437/04)
(30 October 2005)
Overarching Guideline

11. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1111Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1111
CHMP/437/04
• The chosen reference medicinal product must be a medicinal
product authorised in the Community, on the basis of a
complete dossier in accordance with the provisions of Article
8 of Directive 2001/83/EC, as amended.
• The chosen reference medicinal product, defined on the basis
of its marketing authorisation in the Community, should be
used throughout the comparability program for quality, safety
and efficacy studies during the development of a similar
biological medicinal product in order to allow the generation
of coherent data and conclusions.
• Data generated from comparability studies with medicinal
products authorised outside the Community may only provide
supportive information.

12. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1212Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1212
Selection of the originator
• The active ingredient of the biosimilar products must be as similar as
possible from the biological and molecular point of view to the
reference product.
• The pharmaceutical form, the concentration and the administration
route should be the same of the reference product .
• The analysis of the finished product, if available in suitable and useful
amount and quality (excipients, quantity, etc.) allows the
characterisation of the product itself, without gaining information on
the in process results and controls of the originator.
• It has to be remembered that a biological/biotechnological product is
defined not only by its quality attributes but also by the characteristics
of the process and by the results of the in process controls.

13. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1313Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1313
Revision of Guidelines CHMP/437/04
(Overarching Guideline)

14. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1414Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1414
CHMP/437/04 Rev. 1

15. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1515Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1515
Main changes
• Clarification on the “biosimilar” approach
• Choice of the reference product
– Use of non -EEA authorised comparators as
supportive data.
– In this case a comparison between the EEA authorised
reference product, the non –EEA authorised comparator
and the proposed biosimilar should be carried out to
link the three different products
• Principles of establishing biosimilarity have been
expanded and detailed.

16. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1616Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1616
Quality Guidelines
(CHMP/BWP/49348/2005)
• Biological/biotechnological products are macromolecules (up
to quaternary structure) and may undergo post-translational
modification (glycosylation).
• Biochemical and biophysical characterisation can be
performed on a comparative basis with great difficulty (i.e. the
non formulated active substance of the originator to allow
analysis not always available)
• Importance of the manufacturing process details (not
available for the originator)
• Immunogenicity of the biosimilar product as compared to the
originator
• Reference to Comparability Guideline (CPMP/ICH/5721/03)

17. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1717Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1717
Comparability exercise: quality level

18. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1818Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1818
Comparability exercise
• The demonstration of comparability does not necessarily mean
that the quality attributes of the pre-change and post-change
product are identical, but that they are highly similar.
• Comparison is performed that integrates and evaluates all data
collected, e.g., routine batch analyses, in-process control,
process validation/evaluation data, characterisation and
stability.
• The battery of tests for the comparability exercise should be
carefully selected and optimised to maximise the potential for
detecting relevant differences in the quality attributes of the
product
• It might be appropriate to apply more than one analytical
procedure to evaluate the same quality attribute and to add new
tests as a result of changes in quality attributes that the existing
methods are not capable of measuring.

19. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1919Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 1919
Biosimilar Products Guideline Rev.1 - quality

20. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2020Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2020
Main changes
• Better clarification on the formulation issue
• Comparability section enlarged
• The concept of highly similar quality profile has
been introduced
• Some changes in the terminology
• Clarification that minor differences can be
acceptable
• Presence of quantitative and qualitative
differences discussed
• Target acceptance criteria justified
• Evolution of the reference product

21. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2121Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2121
Non Clinical Guidelines
(CHMP/BMWP/42832/2005)
According to the outcome of the analytical evaluation of the
biosimilar:
• Case by case basis
• Non clinical studies can be reduced/omitted if the quality data
are strongly enough to support full biosimilarity
• They should be able to eventually identify specific aspects
which may represent a characteristic not present in the
originator
• in vitro e in vivo surrogate test in relation to specific aspects
• Animal models identical to those used by the originator.

22. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2222Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2222
Clinical Guidelines
(CHMP/BMWP/42832/2005)
According to the outcome of the analytical evaluation
of the biosimilar
• Case by case basis
• End points and surrogate markers chosen on the
basis of the intended efficacy evaluation
• Immunogenicity
– Repeated administration
• The originator and the biosimilar must show the same
efficacy profile.
• A number of product specific guidelines are available

23. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2323Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2323
Concept paper on the revision of
EMA/CHMP/BMWP/572828/2011

24. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2424Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2424
Emerging issues
• The development of more complex biosimilar
medicinal products is challenging, and several issues in
the development are under re-evaluation
• selection of relevant species for non-clinical studies.
• need for clinical equivalence studies and other issues
of the design of the pivotal clinical studies, role of
biomarkers, amount of immunogenicity data needed,
and the possibility to extrapolate to other indications.
• WHO Guidelines
• 3R principle on animal use (replacement, reduction and
refinement)

25. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2525Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2525
Critical issues for biosimilars
• A full and extensive chemical-physical analysis of the
product will hardly be sufficient to demonstrate per
se the similarity between the originator and the new
product
• Manufacturing process fundamental for a
biological/biotechnological product, not available for
the developer of the biosimilar
• in vivo Immunogenicity of the biosimilar is not
predictable as compared to the originator
• The size of the non clinical studies and of the clinical
trials required cannot be easily determined a priori
and could be quite large.

26. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2626Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2626
Biosimilars
At least
• 14 authorised products (such as GH, EPO, G-
CSF, etc.)
• More products approaching including MoAbs

27. Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2727Istituto Superiore di Sanità National Center forIstituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-Immunobiologicals Research and Evaluation-CRIVIBCRIVIB 2727
Conclusions
• Biosimilar products are part of the European legislation and are well
separated from the generic medicinal product concept established for
“chemical entities”
• A number of general as well as specific guidelines are available. They
cover both the initial comparability assessment and the subsequent
development steps in terms of non clinical and clinical issues. Some of
them are under revision.
• The development of an increasing number of biosimilar products has
to be noticed. In particular MoAbs, close to the expiry date of the
patent have been already included in the pipeline
• The Marketing authorisation process at EMA does not foreseen any
less stringent assessment of the quality, safety and efficacy of a
biosimilar product as compared to an originator. Therefore the two
types of products undergo the same procedure under the same strict
scientific and regulatory conditions.