Giordano D. Beretta
Presidente eletto AIOM
Oncologia Medica
Humanitas Gavazzeni Bergamo
The European Medicines Agency (EMA) is a
decentralised agency of the European Union (EU),
located in London.
It began operating in 1995.
The Agency is responsible for the scientific
evaluation, supervision and safety monitoring of
medicines in the EU.
EMA protects public and animal health in 28 EU Member States, as well as the countries of the European Economic Area, by ensuring that all medicines available on the EU market are safe, effective and of high quality
EMA is a networking organisation
whose activities involve thousands of experts from across Europe. These
experts carry out the work of EMA's scientific committees.
EMA is governed by an independent Management Board. Its day-to-day
operations are carried out by the EMA staff, based in London, overseen by
EMA's Executive Director.
The Management Board consists of 36 members, appointed to act in the public interest, who do not represent any government, organisation or sector.
EMA has seven scientific committees that evaluate medicines along their lifecycle from early stages of
development, through marketing authorisation to safety monitoring once they are on the market.
In addition, the Agency has a number of working parties and related groups, which the committees can consult on scientific issues relating to their particular field of expertise.
These bodies are composed of European experts made available by national competent authorities of the EU Member States, which work closely with EMA in the European medicines regulatory network.
Non generici con nome trendy
Molecole complesse ottenute con tecniche di ingegneria genetica
Simili ma non uguali all’«originator»
Intrinsecamente variabili (anche da lotto a lotto)
Bisogna partire dall’ipotesi che sia diverso e dimostrare l’identicità terapeutica
Necessario un confronto con il prodotto di riferimento
Direttiva CE2001/83 art.10, comma 6 del 2004
Il biosimilare può non soddisfare le condizioni della
definizione di medicinale «a causa di differenza attinenti alle materie prime o di differenza nei processi di
produzione del medicinale biologico di riferimento»
A biosimilar is a biological medicinal product that
contains a version of the active substance of an
already authorised original biological medicinal
product (reference
medicinal product) in the EEA.
Similarity to the reference medicinal product in terms of quality characteristics, biological activity, safety and efficacy based on a comprehensive
comparability exercise needs to be established
A biological substance is a substance that is
produced by or extracted from a biological source and that needs for its characterisation and the
determination of its quality a combination of
physico-chemical-biological testing together with the production process and its control.
The active substance of a similar biological
medicinal product is a known biological active
substance and similar to the one of the reference medicinal product.
A similar biological medicinal product and its
reference medicinal product are expected to have the same safety and efficacy profile and are
generally used to treat the same conditions
The reference medicinal product is a medicinal product which has been granted a marketing authorisation by a Member
State or by the Commission on the basis of a complete dossier, i.e. with the submission of quality, pre-clinical and clinical data and to which the application for marketing authorisation for a similar biological medicinal product refers to.
A company may choose to develop a biological medicinal product claimed to be “similar” to a reference medicinal
product, which has been granted a marketing authorisation in the European Economic Area (EEA) on the basis of a complete dossier in accordance with the provisions of Article 8 of
Directive 2001/83/EC, as amended. For this scenario, the legal basis of Article 10(4) of Directive 2001/83/EC and Section 4, Part II, Annex I to the said Directive lays down the
requirements for the Marketing Authorisation Applications (MAAs) based on the demonstration of the similar nature of the two biological medicinal products. Comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality, safety and efficacy, of the similar biological medicinal product and the chosen reference
medicinal product authorised in the EEA.
Weise M ASCO 2016 Educational session
htt p:/ /ww w .em a.europa .eu/ doc s/ en _GB /do cu ment _ li brary /Sc ientif ic _ guideline /2012/06/WC5001 286 86.pdf
Weise M ASCO 2016 Educational session
Secondo aggiornamento nel maggio 2013 ed in consultazione per commenti e suggerimenti fino a novembre 2013
Forniti elementi addizionali su:
Approccio basato sul rischio per il disegno degli studi non clinici
L’uso dei markers farmacodinamici per la dimostrazione della compatibilità clinica
Disegni di studio (non inferiorità vs equivalenza), scelta di una popolazione di pazienti appropriata e scelta di endpoint surrogati nei trial di efficacia
Estrapolazione di efficacia e sicurezza da un’indicazione terapeutica ad un’altra
Maggio 2017
Nel dossier di registrazione che l'Azienda produttrice di un
farmaco presenta ad EMA, sono previsti 5 moduli
Per i prodotti di origine
biotecnologica, nel modulo 3 sono previsti informazioni
aggiuntive per quanto riguarda:
informazioni generali e relative alle materie prime e ai materiali sussidiari, al processo di
fabbricazione della sostanza attiva, alla caratterizzazione della sostanza attiva e al
controllo della sostanza attiva.
Nel modulo 4 devono essere riportati i risultati di studi preclinici (in vitro e in vivo)
nel modulo 5 i risultati di studi di fase I e di fase III ( non sono
richiesti studi di fase II).
Common Technical Document
Applicants should provide in Module 1.5.2, a concise document (up to approximately 5 pages), summarizing the grounds and evidence used for demonstrating that the medicinal product for which an application is
submitted is: A similar biological medicinal product – a so-called ‘Biosimilar’
This summary should include details on the similar
biological medicinal product, its active substance, raw materials and manufacturing process. Differences with relevant attributes of the reference medicinal product should be included. Any other changes introduced
during development which could affect comparability should be highlighted.
The comparability exercise versus the reference
medicinal product for quality, safety and efficacy should be described, and the reference medicinal product used throughout the quality, safety and efficacy development program (as appropriate) should be defined.
Module 2 must include the Quality Overall
Summary, Non-clinical Overview and Clinical Overview. Whenever new additional studies
have been provided within the documentation, Non-clinical and Clinical Summaries should
also be submitted.
It is recommended that the Non-clinical and the Clinical overall Summaries deal with
comparability issues in separate sections in
order to facilitate the regulatory review by
cross referencing the appropriate separate
sections of the dossier which contain the
relevant data.
The standard generic approach (demonstration of
bioequivalence with a reference medicinal product by
appropriate bioavailability studies) which is applicable to most chemically-derived medicinal products is in principle not sufficient to demonstrate similarity of
biological/biotechnology-derived products due to their complexity. The biosimilar approach, based on a
comprehensive comparability exercise, will then have to be followed.
The scientific principles of such a biosimilar comparability exercise are based on those applied for evaluation of the impact of changes in the manufacturing process of a
biological medicinal product (as outlined in ICH Q5E).
Whether the biosimilar approach would be applicable for a certain biological medicinal product depends on the state of the art of analytical methods, the manufacturing
processes employed, as well as the availability of clinical models to evaluate comparability.
The biosimilar approach is more likely to be successfully applied to products that are highly purified and can be thoroughly characterised (such as many biotechnology- derived medicinal products). The biosimilar approach is more difficult to apply to other types of biological
medicinal products, which by their nature are more difficult to characterise, such as biological substances arising from extraction from biological sources and/or
those for which little clinical and regulatory experience has been gained.
The active substance of a biosimilar must be similar, in molecular and biological terms, to the active substance of the reference medicinal product. For example, for an active substance that is a protein, the amino acid sequence is
expected to be the same.
The posology and route of administration of the biosimilar must be the same as those of the reference medicinal
product.
Deviations from the reference product as regards strength, pharmaceutical form, formulation,
excipients or presentation require justification. If needed, additional data should be provided. Any difference should not compromise safety.
Intended changes to improve efficacy (e.g.
glycooptimisation) are not compatible with the biosimilarity approach. However, differences that could have an advantage as regards safety (for instance lower levels of impurities or lower
immunogenicity) should be addressed, but may not preclude biosimilarity.
The biosimilar shall, with regard to the quality data, fulfil all requirements for Module 3 as defined in
Annex I to Directive 2001/83/EC, as amended and satisfy the technical requirements of the European Pharmacopoeia and any additional requirements,
such as defined in relevant CHMP and ICH guidelines.
A complete Module 3 should be submitted in accordance to the requirements set out in the Notice to Applicants.
In addition, Biosimilar applications should also provide a demonstration of comparability, as
discussed in the “Guideline on similar biological medicinal products containing biotechnology- derived proteins as active substance: Quality issues”. Applicants should note that the
comparability exercise for a similar biological
medicinal product versus the reference medicinal product is an additional element to the normal
requirements of the quality dossier and should be
dealt separately when presenting the data.
Comparable safety and efficacy of a biosimilar to its
reference product has to be demonstrated or otherwise
justified in accordance with the data requirements laid down in Directive 2001/83/EC, as amended. General technical and product-class specific provisions for biosimilars are
addressed in EMA/CHMP guidelines (see section 2). For situations where product-class specific guidance is not
available, applicants are encouraged to seek scientific advice from Regulatory Authorities.
If biosimilarity has been demonstrated in one indication, extrapolation to other indications of the reference product could be acceptable with appropriate scientific justification.
There is no regulatory requirement to repeat the
demonstration of biosimilarity against the reference product, e.g. in the context of a change in the manufacturing process, once the Marketing Authorisation has been granted.
In order to support pharmacovigilance monitoring and in accordance with Article 102(e) of Directive 2001/83/EC, as amended, all appropriate measures should be taken to
clearly identify any biological medicinal product which is the subject of a suspected adverse reaction report, with due
regard to its brand name and batch number.
For a similar biological of a reference medicinal product, Art 10, results of pre-clinical and clinical studies should be provided as appropriate
following the CTD structure.
The requirements to demonstrate safety and efficacy of similar biological medicinal products have to comply with the data requirements laid down in Annex I to Directive 2001/83/EC.
General and product-class specific requirements are addressed in EMEA/CHMP guidelines. For
situations where product-class specific guidance is not available, Applicants are encouraged to seek scientific advice from EU Regulatory Authorities.
As for any other application, it should be noted that the responsibility for the quality of the
submitted documentation lies with the Applicant
and is crucial to the overall process.
the primary objective in evaluating an Article
10(4) application is to determine the similarity (or not) of a given biological medicinal product to a reference medicinal product.
The comparability exercise should be a robust head-to-head comparison between the similar biological medicinal product and the reference medicinal product performed at the levels of quality, safety and efficacy.
Due to the diversity of biological medicinal
products, the assessment of Biosimilar products should be done on a case-by-case basis. The
amount of data required will take into account the
specific characteristic of each individual medicinal
product.
Quality comparison
Highly technology-dependent
Cell culture, impurities – product and process related, sterilisation methods, presence or absence of serum albumin, glycosylation pattern…
Non-clinical comparison
In vitro receptor binding & cell- based assays are fundamental
(where model allows) In vivo PK/PD/activity/toxicity
Clinical comparative studies
Most sensitive population and endpoints (healthy volunteers and/or PK/PD/biomarker data may suffice)
“Equivalence” study with justified margins (δ)
6-12 month safety data (incl.
immunogenicity)
Extrapolation of indications !!
Similarity rather than S/E per se
Normally, similar clinical efficacy should be demonstrated in adequately powered, randomised, parallel group
comparative clinical trial(s), preferably double-blind, normally equivalence trials.
[…]The guiding principle is to demonstrate similar clinical efficacy and safety compared to the reference medicinal product, not patient benefit per se, which has already been shown for the reference medicinal product.
[…] In general the most sensitive patient population and clinical endpoint is preferred to be able to detect product- related differences, if present and, at the same time, to reduce patient and disease-related factors to a minimum in order to increase precision.
A clinical trial in a homogeneous patient population with a clinical endpoint that measures activity as primary
endpoint may be considered.
An example may be Overall Response Rate.
European Medicines Agency 30 May 2012
Guideline on similar biological medicinal products containing monoclonal antibodies – non-clinical and clinical issues
27 aprile 2017
The evidence acquired over 10 years of clinical experience shows that biosimilars
approved through EMA can be used as safely and effectively in all their approved indications as other biological medicines.
Because biosimilars are made in living organisms there may be some minor
differences from the reference medicine.
These minor differences are not clinically
meaningful, i.e. no differences are expected in safety and efficacy.
Natural variability is inherent to all biological
medicines and strict controls are always in
place to ensure that it does not affect the way
the medicine works or its safety.
Biosimilars are approved according to the same standards of pharmaceutical quality, safety and efficacy that apply to all biological medicines approved in the EU.
The aim of biosimilar development is to
demonstrate biosimilarity - high similarity in terms of structure, biological activity and
efficacy, safety and immunogenicity profile.
By demonstrating biosimilarity, a biosimilar can rely on the safety and efficacy experience gained with the reference medicine. This
avoids unnecessary repetition of clinical trials already carried out with the reference
medicine.
If a biosimilar is highly similar to a reference
medicine, and has comparable safety and efficacy in one therapeutic indication, safety and efficacy data may be extrapolated to other indications
already approved for the reference medicine.
Extrapolation needs to be supported by all the scientific evidence generated in comparability studies (quality, non-clinical and clinical).
Extrapolation is not a new concept but a well- established scientific principle used routinely
when biological medicines with several approved indications undergo major changes to their
manufacturing process (e.g. to introduce a new formulation). In most of these cases, clinical trials are not repeated for all indications and changes are approved based on quality and in vitro
comparability studies.
Safety of biosimilars is monitored through pharmacovigilance activities, in the same way as for any other medicine.
There is no specific safety requirement applicable only to biosimilars because of their different development route.
Over the last 10 years, the EU monitoring system for safety concerns has not
identified any relevant difference in the nature, severity or frequency of adverse effects between biosimilars and their
reference medicines.
DEFINITIONS
Interchangeability refers to the possibility of exchanging one
medicine for another medicine that is expected to have the same clinical effect. This could mean replacing a reference product with a biosimilar (or vice versa) or replacing one
biosimilar with another.
Replacement can be done by:
Switching, which is when the
prescriber decides to exchange one medicine for another medicine with the same therapeutic intent.
Substitution (automatic), which is the practice of dispensing one medicine instead of another equivalent and interchangeable medicine at
pharmacy level without consulting the prescriber.
EMA does not regulate
interchangeability, switching and substitution of a
reference medicine by its biosimilar.
These fall within the remit of EU Member States.
Over the last 10 years, the EU monitoring system for safety
concerns has not identified any
relevant difference in the nature,
severity or frequency of adverse
effects between biosimilars and
their reference medicines.
giordano.beretta@gavazzeni.it
