Q&A 11-20: Similar biological product applications

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11. What fee do I have to pay and how is the appropriate fee for my application calculated? Rev. December 2015

Fees for obtaining and maintaining a Community authorisation to market medicinal products for human use are levied in accordance with Regulation (EC) No 297/95.

For information on the fee applicable for applications according to Article 10(4) of Directive 2001/83/EC (“similar biological”), please refer to the explanatory note on fees payable to the European Medicines Agency.

For Post-Authorisation applications (extension applications, Type IA/IB, Type II, Renewals) the same fees as for any other medicinal product will apply. This includes the possibility for a reduced fee when the extension application only concerns quality data.

Payment of fees

The fee will become due on the date of the notification of the administrative validation to the applicant and fees will be payable within 45 calendar days of the date of the said notification.

After approximately 15 days an invoice will be sent to the applicants billing address held on the Agency’s file.

The invoice will contain details of the product and type of procedure involved, the fee amount, the customer purchase order number associated with the procedures invoiced and financial information.

Applicants requiring a purchase order number or similar references on the invoice are requested to clearly indicate it on the cover letter or application form accompanying the dossier. The Agency does not accept stand-alone notifications of purchase order numbers that are not associated with a dossier. Applicants not requiring a purchase order number on the invoice should also clearly state this in the cover letter. Applicants are requested to provide this information in the cover letter.

The Agency’s contacts point for any queries on fee payment are:

Product and Application Business Support (PA-BUS): pa-bus@ema.europa.eu

Fee waivers / reductions

In addition to the reduced fees provided for in the Fee Regulation, fee deferrals, waivers or further fee reductions may be granted to:

  • Applicants which meet the definition of a micro, small or medium-sized enterprise (SME)
  • Medicinal products designated as “orphan medicinal product”
  • Multiple applications on usage patent grounds

In addition, fee reductions may be granted by the EMA Executive Director in exceptional circumstances and for imperative reasons of public health, after consultation of the relevant scientific committee. This also applies in cases where an applicant disagrees on the classification by the EMA of an application under one of the fee categories described in the Fee Regulation.

References:

12. What is the fee for a GMP/GCP inspection?

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

13. When could a fee waiver / fee reduction be granted?

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

14. How shall I present my similar biological medicinal product application (format)?

Marketing authorisation applications for a similar biological medicinal product should follow the structure of the CTD format, as for any other marketing authorisation application. Specific requirements that such applications should fulfil are listed below:

Module 1

  • 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’ (Art 10.4).

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. Please note that the reference medicinal product used in the comparability exercise should have been authorised in the EEA.

Applicants should note that the chosen reference medicinal product used in the comparability exercise should have been authorised in the Union. (Please refer to Question 5. “What is the comparability exercise”?).

The table “Overview of the chosen reference product for comparability" should be completed and included in Module 1.5.2

An EU Risk Management Plan is required (Please refer to Question 39. “Should I submit an EU Risk Management Plan as part of my similar biological medicinal product application?”).  

All the other requirements of Module 1 apply also to similar biological medicinal products with the exception of the paediatric requirements set out in Articles 7 and 8 of the Paediatric Regulation.

When certain elements are not included, a justification for its absence should be provided in the respective section.

Module 2

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.

Module 3

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. The detailed location of this data within the CTD structure can be discussed with the EMA prior to submission, but it is recommended to make use of section 3.2.R.

Section 3.2.A. should be provided as appropriate, giving information about Facilities and Equipment and Safety Evaluation of Adventitious Agents.

For all applications, the table A on ‘Materials of animal origin covered by the Note for Guidance on minimizing the risk of transmitting animal spongiform encephalopathy agents via medicinal products should be completed and included in Module 3.2.R, stating not applicable, if relevant.

For materials of animal origin other than those covered by the Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products, Applicants are requested to complete the table B on ‘Other materials of animal origin’.

If an application relates to a medicinal product, which contains or uses in the manufacture materials of human origin, Applicants are request to complete the table C on albumin and other human tissue derived products.

Module 4 and Module 5

For a similar biological of a reference medicinal product, Art 10 (4), 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.

For queries related to the presentation of the application, please contact the EMA. Alternatively, Applicants may request a Pre-Submission Meeting with the EMA to clarify any outstanding points. 

References:

15. When can I submit my similar biological medicinal product application considering the protection period of the reference medicinal product?

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 (Please refer to Question 3. “What is the legal basis for my application?” and Question 4. “What is the so-called ‘reference medicinal product’ referred to in the application for a similar biological medicinal product?”).

For similar biological application submitted through the Centralised Procedure, when referring to:

  • a centrally authorised reference medicinal product, the 10-year or 8-year protection period, as applicable, should have expired  and the eligibility should have been confirmed (Please refer to Question 2. “Is my similar biological medicinal product eligible for evaluation under the Centralised Procedure?”). The relevant protection period should be counted1 as starting from the date of notification of the marketing authorisation decision to the MAH and can be found in the Official Journal of the European Union as well as in the Community register of medicinal products for human use on the European Commission website; as an example, a similar biological application of a reference medicinal product notified on Day A, could be submitted 10 or 8 years later than Day A+1, as applicable;
  • a nationally authorised reference medicinal product, the 6/10-year protection period, depending on the Member State which has granted the marketing authorisation or 8-year protection period, as applicable, should have expired and the eligibility should have been confirmed (Please refer to Question 2.  “Is my similar biological medicinal product eligible for evaluation under the Centralised Procedure?”).  However, a similar biological application based on a nationally authorised reference medicinal product can only be processed via the Centralised Procedure after expiry of a 10-year period of protection if the reference medicinal product chosen by the Applicant is also authorised in Member States where a ten-year period of protection applies.

Notion of ‘global marketing authorisation’

The calculation of the protection period should take into account the notion of global marketing authorisation.

The global marketing authorisation contains the initial authorisation and all variations and extensions thereof, as well as any additional strengths, pharmaceutical forms, administration routes or presentations authorised through separate procedure and under a different name, granted to the Marketing Authorisation Holder of the initial authorisation.

This means that for a reference medicinal product, the start of the data exclusivity and market protection periods is determined by the first MA in the Union which was granted in accordance with the relevant European pharmaceutical legislation (Acquis Communitaire).

In case of any doubt, the Applicant can liaise with the EMA provided detailed information is given.

The new protection periods of ‘8+2+1’ applies only to reference medicinal products for which the marketing authorisation application has been submitted as of 30 October 2005 for MRP, DCP and national procedures and as of 20 November 2005 for Centralised Procedure according to the revised European legislation.

In line with the revised rules mentioned above, applications for similar biological medicinal products can be submitted after expiry of the data exclusivity period for the reference medicinal product i.e. 8 years after the date of notification of the authorisation of the reference medicinal product to the MAH. However, the authorised similar biological product can only be placed on the market 10 or 11 years after expiry of the market protection period applicable for the reference medicinal product.

1The rules applicable to periods, dates and time limits can be found in Regulation no 1182/71

References:

16. Can I submit my similar biological medicinal product application even if some parts of the product information of the reference medicinal product are covered by usage patents?

Companies use patent law to obtain further protection for an innovative medicine in some or all Member States. This protection applies e.g. to new uses of the medicine, such as new indications and pharmaceutical forms. While this ‘usage patent’ protection is in place, a similar biological medicine cannot be marketed for the protected indication or pharmaceutical form, even if the period of data and market exclusivity of the reference medicinal product has expired.

Applications for marketing authorisation for similar biological medicinal products can however be submitted and authorised even if some parts of the product information of the reference medicinal product are covered by patent law.

Article 11 of Directive 2001/83/EC and Article 3.3(b) of Regulation No 726/2004 allow Applicants/Marketing Authorisation Holders to exclude from their proposed product information those parts of the SmPC of the reference medicinal product referring to indications or dosage forms still covered by patent law.

References:

17. If the patent situation differs in the various Member States how will this be reflected in the product information of my similar biological medicinal product? Rev. December 2015

It is not possible to have different product information for a particular medicinal product authorised via the Centralised Procedure, to take account of different patent situations in the various Member States.

However, in order to facilitate the access to the Centralised Procedure for similar biological products, duplicate applications may be requested to the European Commission on grounds of the existence of patents protecting certain therapeutic indications or pharmaceutical forms.

The duplicate application may contain more or fewer indications or pharmaceutical forms than the original application/marketing authorisation when this is necessary to market the product in Member States where a specific indication or pharmaceutical form is protected by patent law.

However, in order to maintain the harmonisation of the SmPCs, the Applicant should commit as part of the marketing authorisation application, to extend the indication(s)/pharmaceutical form(s) of the duplicate marketing authorisation as soon as the patent restrictions no longer exist or should commit to withdraw the marketing authorisation with restricted indications/pharmaceutical forms when the relevant patents are no longer in force.

Multiple marketing authorisation applications and post-authorisation activities for similar biological medicinal products, justified on the basis of existing patent protection for the reference medicinal product, are eligible to fee incentives. Please, see “Explanatory note on fees payable to the European Medicine Agency” 

References:

18. If a therapeutic indication is covered by patent law which sections of the SmPC can be deleted in connection with the patented indication?

Information directly related to the patented indication can be deleted from sections 4.1. therapeutic indications, 4.2. posology and method administration and 5.1. pharmacodynamic properties of the summary of product characteristics.

For public health reasons, safety related information in sections 4.3 to 4.8. of the SPC should be maintained.

If the Applicant wishes to omit other information than the one mentioned above directly related to the patented indication, this must be properly justified.

19. How can I update the product information of my similar biological medicinal product after expiry of the patent of the reference medicinal product?

The appropriate type IB variation should be submitted to align the product information of the similar biological medicinal product with the product information of the reference medicinal product, following expiry of the patent.

References:

20. When shall I submit mock-ups and/or specimens?

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

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