Istituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-CRIVIB 1

Key issues on Biosimilars

Guidelines development and

current revision trends

Istituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-CRIVIB 2

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

Istituto Superiore di Sanità National Center for Immunobiologicals Research and Evaluation-CRIVIB 3

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

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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

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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.

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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

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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.

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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 , 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

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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

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Guideline on similar biological

medicinal products (CHMP/437/04)

(30 October 2005)

Overarching Guideline

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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.

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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.

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Revision of Guidelines CHMP/437/04

(Overarching Guideline)

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CHMP/437/04 Rev. 1

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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.

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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)

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Comparability exercise: quality level

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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.

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Biosimilar Products Guideline Rev.1 - quality

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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

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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.

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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

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Concept paper on the revision of

EMA/CHMP/BMWP/572828/2011

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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)

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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.

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Biosimilars

At least

• 14 authorised products (such as GH, EPO, G-

CSF, etc.)

• More products approaching including MoAbs

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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.