Questions 1-10: Similar-biological-product applications

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This page lists questions 1 to 10 of the European Medicines Agency's regulatory and procedural questions on biosimilar medicines.

For further information on these questions and answers, see questions and answers: similar-biological-product applications.

The remaining questions are available below:

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1. What is a similar biological medicinal product?

A similar biological medicinal product, also known as a biosimilar, is a product that is similar to a biological medicine that has already been authorised, the so-called 'reference medicinal product'.

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. (Refer to question 43: Will my similar biological medicinal product be considered interchangeable with the reference medicinal product?

In principle, the concept of similar biological medicinal product is applicable to any biological product. However, in practice, the success of such a development approach will depend on the ability to characterise the product and therefore to demonstrate the similar nature of the concerned products.

Definition of biological medicinal products

According to Part I of Annex I of Directive 2001/83/EC, a biological medicinal product is a product that contains a biological substance. A biological substance is a substance that is produced by or extracted from a biological source and that needs a combination of physico-chemical-biological testing together with the production process and its control for its characterisation and the determination of its quality.

For example, recombinant proteins, monoclonal antibodies, medicinal products derived from human blood and human plasma, immunological medicinal products and advanced therapy medicinal products should be considered biological medicinal products.

References

2. Is my similar biological medicinal product eligible for evaluation under the centralised procedure?

Regulation (EC) No 726/2004 creates a centralised procedure for the authorisation of medicinal products, for which there is a single application, a single evaluation and a single authorisation allowing direct access to the single European Union market. The types of products, which fall within the scope of the Regulation, are set out in Article 3 and the Annex to that Regulation.

For similar biological medicinal products, also known as biosimilars, eligibility can be granted to the centralised procedure as follows:

1. Mandatory scope of the centralised procedure

The mandatory scope of the centralised procedure is set up in Article 3(1) of Regulation (EC) No 726/2004. According to this Article, medicinal products developed by means of biotechnological processes as described in the Annex (point 1) of Regulation (EC) No 726/2004 should be authorised by the Community.

The reference medicinal product could be a product authorised via a national or mutual-recognition procedure or the centralised procedure.

2. Optional scope of the centralised procedure

The optional scope for a similar biological medicinal product is applicable when the product does not fall under the mandatory scope of the centralised procedure, as explained above. Two situations can be found:

2.1. Similar biological medicinal product of a centrally authorised product 

Similar biological medicinal product applications of medicinal products authorised via the centralised procedure have automatic access to the centralised procedure under Article 3(3) of Regulation (EC) No 726/2004. 

2.2. Similar biological medicinal product of a national, mutual-recognition-procedure or decentralised-procedure product

Similar biological medicinal products that do not fall under the mandatory scope can, at the request of the applicant, be accepted for consideration under the centralised procedure Article 3(2)(b), when the applicant shows that the medicinal product constitutes:

  • a significant therapeutic, scientific or technical innovation;
  • the granting of a Community authorisation for the medicinal product is in the interest of patients at Community level.

For further guidance, reference is made to the guideline on Article 3(2) of Regulation (EC) No 726/2004 – Optional scope of the centralised procedure.

Regardless of whether the product falls into the mandatory or optional scope, an eligibility request should always be submitted using the specific form and accompanied by a justification of eligibility for evaluation under the centralised procedure.

When submitting this request, the Applicant should use the pre-submission request form (eligibility) and send it electronically to cpeligibility@ema.europa.eu, accompanied by the draft summary of product characteristics and a justification for eligibility. This justification is especially required for medicinal products falling under the optional scope of Article 3(2)b.

Before submission of the dossier, applicants should notify the Agency of their intention to submit an application, preferably six to 18 months in advance (see pre-submission guidance on letter of intention and documentation). The eligibility request can also be submitted as part of this letter of intent to submit.

For similar biological applications of a centrally authorised product, the applicant should state in the letter of intention to submit that they have automatic access to the centralised procedure under Article 3(3).

The Agency will inform the applicant on the outcome of the eligibility request.

Eligibility for duplicate marketing authorisations

The eligibility request should also be submitted for duplicate similar biological marketing authorisations.

At the time of the request for eligibility, the name proposed by the applicant for the duplicate should be different from the name of the original similar biological medicinal product.

References

3. What is the legal basis for my application?

The legal requirements and the procedures for making an application for a marketing authorisation are set out in Directive 2001/83/EC and in Regulation (EC) No 726/2004.

For similar biological applications, the legal basis can be found in Article 6 of Regulation (EC) 726/2004 and Article 10(4) of Directive 2001/83/EC.

It should be noted that at the time of submission of the similar biological application, the protection period of the reference medicinal product should have expired in order to allow the applicant to rely on the dossier of the reference medicinal product.

The reference medicinal product should have been authorised under Article 6 of Directive 2001/83/EC for not less than eight years in a Member State or in the European Union (EU). This period of eight years from initial authorisation of the reference medicinal product, providing a period of so-called data exclusivity, applies only for reference medicinal products for which the marketing authorisation application has been submitted as of 30 October 2005 for mutual-recognition, decentralised and national procedures and as of 20 November 2005 for centralised procedure according to the revised European Union legislation. Please refer to question 15: When can I submit my similar biological medicinal product application considering the protection period of the reference medicinal product?

A similar biological application refers to information that is contained in the dossier of the authorisation of the reference medicinal product, for which a marketing authorisation has been granted in the EU on the basis of a complete dossier.

According to Article 10(4) of Directive 2001/83/EC, where a biological medicinal product that is similar to a reference biological medicinal 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 preclinical 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 Annex I and the related detailed guidelines.

References

4. What is the so-called ‘reference medicinal product’ referred to in the application for a similar biological medicinal product? (Updated October 2014)

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. Applicants will have to identify in the application form for the similar biological medicinal product the reference medicinal product (product name, strength, pharmaceutical form, MAH, first authorisation, Member State/Union), as follows:

  1. The medicinal product which is or has been authorised in the EEA, used as the basis for demonstrating that the data protection perioddefined in the European pharmaceutical legislation has expired (Please refer to question 15: When can I submit my similar biological medicinal product application considering the protection period of the reference medicinal product?).

    This reference medicinal product, identified for the purpose of calculating expiry of the period of data protection, may be for a different strength, pharmaceutical form, administration route or presentation than the similar biological medicinal product.

  2. The medicinal product, the dossier of which is cross-referred to in the similar biological application (product name, strength, pharmaceutical form, MAH, marketing authorisation number). This reference medicinal product may have been authorised through separate procedures and under a different name than the reference medicinal product identified for the purpose of calculating expiry of the period of data protection. The product information of this reference medicinal product will, in principle, serve as the basis for the product information claimed for the similar biological medicinal product.
  3. The medicinal product (product name, strength, pharmaceutical form, MAH, Member State of source) used for the comparability exercise. In Module 1.5 of the dossier, Applicants will be requested to complete a table, indicating the chosen reference medicinal product used for the comparability exercise. (Please refer to question 5: What is the comparability exercise?)

1.0 Source of the reference medicinal product and global development

With the aim of facilitating the global development of biosimilars and to avoid unnecessary repetition of clinical trials, it may be possible for an Applicant to compare the biosimilar medicinal product in certainclinical studies and in in vivo non-clinical studies (where needed) with a non-EEA authorised comparator (i.e. a non-EEA authorised version of the reference medicinal product) which will need to be authorised by a regulatory authority with similar scientific and regulatory standards as EMA (e.g. ICH countries).

Under this approach, it will be the applicant's responsibility to establish that the batches sourced outside the EEA is representative of the reference medicinal product authorised in the EEA through an extensive analytical comparison.

For demonstration of biosimilar comparability at the quality level, side-by-side analysis of the biosimilar product (from commercial scale and site) with EEA authorised reference product must be conducted. However, combined use of non-EEA authorised comparator and EEA authorised reference product is acceptable for the development of the Quality Target Product Profile of the biosimilar product.

If certain clinical and in vivo non-clinical studies of the development programme are performed with the non-EEA authorised comparator, the Applicant should provide adequate data or information to scientifically justify the relevance of these comparative data and establish an acceptable bridge to the EEA-authorised reference product. As a scientific matter, the type of bridging data needed will always include data from analytical studies (e.g., structural and functional data) that compare all three products (the proposed biosimilar, the EEA-authorised reference product and the non EEA-authorised comparator), and may also include data from clinical PK and/or PD bridging studies for all three products. The overall acceptability of such an approach and the type of bridging data needed will be a case-by-case/product-type decision, and is recommended to be discussed upfront with the Regulatory Authorities.However, the final determination of the adequacy of the scientific justification and bridge will only be made during the assessment of the application.

This approach is reflected in the revised Guideline on similar biological medicinal products (CHMP/437/04 Rev 1). This global development approach may be applied by applicants as of adoption of the revised guideline by CHMP.

For further guidance on data requirements, please refer to the relevant general and product-specific guidelines.

References

5. What is the comparability exercise?

According to Article 10(4) of Directive 2001/83/EC, when a biological medicinal product that is similar to a reference biological medicinal product does not meet the conditions in the definition of generic medicinal products, the results of appropriate preclinical tests and clinical trials must be provided. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Annex I of Directive 2001/83/EC and the related detailed guidelines.

Within the European Union regulatory framework, 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. The relevant general and product-specific guidelines should be followed.  Please refer to question 14: How shall I present my similar biological medicinal product application (format)?

References

6. How will I know if the proposed (invented) name of my similar biological medicinal product is acceptable from a public health point of view?

For similar biological medicinal products the same criteria apply as for any other medicinal products in respect to the acceptability of the proposed name by the Name Review Group (NRG). Please refer to the presubmission guidance question 4: How will I know if the proposed invented name of my medicinal product is acceptable from a public health point of view?

The use of a single name is also a requirement for similar biological medicinal products regardless of whether the applicant or marketing-authorisation holder (MAH) wishes to use an invented name, or a common name or scientific name together with a trademark or the name of the MAH.

It should be noted that the applicant or MAH will be required to identify the reference medicinal product and the legal basis for submission of the application within the invented-name notification.

The Name Review Group should also be consulted where the applicant or MAH wishes to use the common or scientific name, together with a trademark or the name of the MAH. In such cases, the applicant or MAH should take into account the rules stated in the guideline on the acceptability of invented names for human medicinal products processed through the centralised procedure.

In addition, the applicant should also note that the international non-proprietary name (INN) designation is within the responsibility of the World Health Organization (WHO). The applicant or MAH should consider the WHO policy on INNs to decide whether it is appropriate to apply the INN used for the reference medicinal product or whether to request a new INN from the WHO.

If, during the assessment of the submitted data, the Agency considers that the proposed INN is not suitable, the applicant or MAH should be prepared to justify their choice of INN. The applicant or MAH may be recommended to contact the WHO to apply for a new INN.

The requirement for a single name for a similar biological medicinal product of a reference medicinal product authorised through the centralised procedure also applies if the reference medicinal product is authorised by Member States via the mutual-recognition or decentralised procedure.

For further information see presubmission guidance for users of the centralised procedure.

References

6.1. What are the dates for submission of invented-name requests?

See presubmission guidance for users of the centralised procedure.

7. How shall I compose the complete name of my medicinal product?

See presubmission guidance for users of the centralised procedure.

8. Is a product identified as a similar biological medicinal product?

Similar biological medicinal products are approved under the same standards of quality, safety and efficacy as any other medicinal product. The summary of product characteristics (SmPC) structure does not have a section to explicitly indicate the legal basis under which a product has been approved. This information is publicly available in the European public assessment report. However, for similar biological medicinal products, the following statement can be found under section 5.1 of the SmPC: '(Invented) Name is a biosimilar medicinal product. Detailed information is available on the website of the European Medicines Agency http://www.ema.europa.eu”.

9. What legal status can I obtain for my medicinal product?

See presubmission guidance for users of the centralised procedure.

10. When and how are rapporteur and co-rapporteur appointed? - Rev. March 2013

The principles outlined in Section 2 of the paper “CHMP Rapporteur/Co-Rapporteur appointment: principles, objective criteria and methodology” shall apply.

However, due to the particularities of the similar biological medicinal product applications (e.g. legal basis, data requirements), the following principles shall be considered on the appointment of CHMP/PRAC Rapporteurs/Co-Rapporteurs and their assessment teams:

  • For the scientific evaluation of a similar biological medicinal product CHMP and PRAC Rapporteurs and Co-Rapporteurs will be appointed.

Methodology on the appointment of Rapporteur/Co- Rapporteur and their assessment teams for similar biological medicinal products

Normally, for similar biological medicinal product applications the appointment procedure of Rapporteur/Co-Rapporteur and her/his assessment team will be initiated as early as 7 months prior to the MAA submission date, to allow Rapporteur /Co-Rapporteur appointment 6 months prior to the MAA intended submission date. At the same time the PRAC (Co-) Rapporteurs will be identified.

The methodological steps for the appointment procedure of Rapporteur/Co-Rapporteur (where relevant) and their assessment teams as outlined in Section 4.2 of the paper “CHMP Rapporteur/Co-Rapporteur appointment: principles, objective criteria and methodology” shall apply.

Re-examination of a CHMP Opinion of a similar biological medicinal product

Legal Framework

  • Article 62(1) of Regulation (EC) No 726/2004 of 31 March 2004 (fourth subparagraph).

The principles and the methodology on the re-examination of a CHMP Opinion as outlined in Section 5.1 of the paper “CHMP Rapporteur/ (Co) Rapporteur appointment: principles, objective criteria and methodology” shall apply.

See web-link: EMA pre-submission guidance for users of the centralised procedure - List of questions

References

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