Generic / hybrid applications: questions 11 to 22

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This page lists questions 11 to 22 of the European Medicines Agency's questions and answers on generic and hybrid applications.

The page is updated regularly to reflect new developments, to include guidance on further pre-authorisation procedures and to reflect the implementation of new European legislation. Revised topics are marked 'New' or 'Rev.' on publication.

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11. How shall I present my generic or hybrid application (format)?

Marketing Authorisation Applications for a generic/hybrid 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 ‘generic’ of a reference medicinal product (Art 10.1). This summary should include details on the medicinal product, its qualitative and quantitative composition in active substance(s), its pharmaceutical form and its safety/efficacy profile of the active substance(s) in comparison to the active substance(s) of the reference medicinal product, as well as details related to the bio-availability and bio-equivalence, where necessary, of the medicinal product concerned.
  • A so-called ‘hybrid’ of a reference medicinal product (Art 10.3). This summary should include details on the medicinal product, its active substance, pharmaceutical form, strengths, therapeutic indications, route of administration as appropriate in comparison to the reference medicinal product, as well as details related to the bio-availability and bio-equivalence, where necessary, of the medicinal product concerned.
  • EU Risk Management Plan.

All the other requirements of Module 1 apply also to generic/hybrid 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. Non-clinical and Clinical Summaries can be provided, but they are only mandatory if new additional studies have been provided within the documentation. The non-clinical and clinical overviews should particularly focus on the following elements:

  • A summary of impurities present in batches of the active substance(s) (and where relevant decomposition products arising during storage) as proposed for use in the product to be marketed;
  • An evaluation of the bioequivalence studies or a justification why studies were not performed with respect to the guideline on the investigation of bioequivalence
  • An update of published literature relevant to the substance and the present application. It may be acceptable for articles in "peer review" journals to be annotated for this purpose.
  • Every claim in the Summary of Product Characteristics (SPC) not known from or inferred from the properties of the medicinal product and/or its therapeutic group should be discussed in the non-clinical/clinical overviews/summaries and substantiated by published literature and/or additional studies.
  • When different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of the active substance of the reference medicinal product are used, additional information providing proof that their safety and/or efficacy profile is not different from the one of the reference medicinal product should be submitted

Module 3

A complete Module 3 should be submitted in accordance to the requirements set out in the Notice to applicants.

For all applications, the table A on ‘Materials of animal origin covered by the Notice 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.

Module 4 and Module 5

  • For a ‘generic’ of a reference medicinal product (Art 10.1) it is not required to provide the results of toxicological and pharmacological tests or the results of clinical trials. The results of the bioequivalence studies performed where appropriate should be included in section 5.3.1. When different salts, esters, ethers, isomers, mixtures of isomers, complexes or derivatives of the active substance of the reference medicinal product are used, additional information providing proof that their safety and/or efficacy profile is not different from the one of the reference medicinal product should be submitted following the CTD structure.
  • For a so-called ‘hybrid’ of a reference medicinal product (Art 10.3), the results of appropriate preclinical and clinical tests should be provided in accordance to the requirements set out in the notice to applicants.

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

12. When can I submit my generic or hybrid application considering the protection period of the reference medicinal product?

At the time of submission of the generic or hybrid 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 (see questions 2 and 3).

For generic and hybrid applications submitted through the centralised procedure:

  • when referring to a centrally authorised medicinal product, the 10- or eight-year protection period, as applicable, should have expired and the eligibility should have been confirmed (see question 1). The relevant protection period should be counted1 as starting from the date of notification of the marketing-authorisation decision to the marketing-authorisation holder 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. As an example, a generic application of a reference medicinal product notified on Day A, could be submitted 10 or eight years later than day A+1, as applicable;
  • a nationally authorised reference medicinal product, the six- or 10-year protection period, depending on the Member State that granted the marketing authorisation, or eight-year protection period, as applicable, should have expired and the eligibility should have been confirmed (see question 1). However, a generic 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 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 a 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 marketing authorisation in the Union that was granted in accordance with the relevant European pharmaceutical legislation (acquis communitaire).

In case of doubt, the applicant can liaise with the Agency, provided that detailed information is provided.

The new protection periods of '8+2+1' applies only to reference medicinal products for which the marketing-authorisation application was submitted from 30 October 2005 for mutual-recognition, decentralised and national procedures and from 20 November 2005 for centralised procedure according to the revised European legislation.

In line with the revised rules mentioned above, applications for generic or hybrid medicinal products can be submitted after expiry of the data-exclusivity period for the reference medicinal product,  i.e. eight years after the date of notification of the authorisation of the reference medicinal product to the marketing-authorisation holder. However, the authorised generic or hybrid product can only be placed on the market ten or 11 years after expiry of the market-exclusivity period applicable for the reference medicinal product.

References


1The rules applicable to periods, dates and time limits can be found in Regulation (EEC, Euratom) No 1182/71.

13. What if my reference medicinal product is an orphan medicinal product?

If the reference medicinal product in support of your generic or hybrid application is an authorised orphan medicinal product, you will have to consider, in addition to the expiry of the data exclusivity (explained in question 12 above) the expiry of the market-exclusivity period for the reference medicinal product.

Article 8(1) of Regulation (EC) No 141/2000 (the Orphan Regulation) provides for a 10-year period of market exclusivity for orphan medicinal products, during which competent authorities cannot accept applications for marketing authorisation for the same therapeutic indication in respect of a similar medicinal products. As explained in the Commission guideline on aspects of the application of Article 8(1) and 8(3) of Regulation (EC) No 141/2000, if the application concerns a generic medicinal product, similarity is assumed. Consequently, the application cannot be validated before the end of the period of market exclusivity unless justification is provided to support one of the derogations laid down in Article 8(3).

This 10-year period of market exclusivity can, however, be reduced to six years if, at the end of the fifth year, it is established that the criteria for orphan designation are no longer met (Article 8(2) of the Orphan Regulation) or extended to 12 years in case of compliance with a paediatric investigation plan, in accordance with Article 37 of Regulation (EC) No 1901/2006 (the Paediatric Regulation).

Therefore, irrespective of whether the reference medicinal product benefits from a period of data exclusivity of 10 or eight years, it will not be possible to validate an application for a generic medicinal product before the end of the market-exclusivity period for the reference medicinal product, unless justification is provided to support one of the derogations laid down in Article 8(3) of the Orphan Regulation.

The period of market exclusivity should be counted as starting from the date of notification of the marketing-authorisation decision to the marketing-authorisation holder, which can be found in the Official Journal of the European Union as well as in the Community register of medicinal products for human use.

Applicants will also have to consider whether the reference medicinal product includes more than one designated orphan condition, as in such cases, a separate 10-year period of market exclusivity will apply for the orphan therapeutic indications granted for the separate orphan condition, starting on the date of the notification of the authorisation of the respective therapeutic indications. Therefore, these therapeutic indications can only be included in the proposed product information for the generic medicinal product after expiry of the respective period of market exclusivity, unless justification is provided to support one of the derogations laid down in Article 8(3) of the Orphan Regulation.

However, where the marketing-authorisation holder of the reference medicinal product applies subsequently for another subset of the same designated orphan condition, the medicinal product will not benefit from any additional period of market exclusivity for that second authorised therapeutic indication.

References

14. When will I have to submit a similarity and, where applicable, derogation report in the context of my generic or hybrid application?

You will have to submit a similarity report in the context of your generic or hybrid application where there are authorised orphan medicinal products under market exclusivity for a condition related to the therapeutic indication proposed in your application.

In advance of submission of your application for marketing authorisation, you are advised to check the Community register of orphan medicinal products  for information on medicinal products designated as orphan.

You will have to indicate in the application form (section 1.2.2) if any medicinal product has been designated as an orphan medicinal product for a condition relating to the therapeutic indication proposed in your application and if applicable, specify the respective orphan-designation number.

If any of the designated orphan medicinal products has been granted a marketing authorisation in the Union, and a period of market exclusivity is in force, you will have to provide a similarity report in module 1.7.1 addressing the possible similarity between your medicinal products and the orphan medicinal products that have received a marketing authorisation.

This legal requirement arises from Article 8(1) of the Regulation (EC) No 141/2000 (the Orphan Regulation), which provides that where a marketing authorisation in respect of an orphan medicinal product is granted, the Agency and the Member States shall not, for a period of 10 years, accept another application for a marketing authorisation, or grant a marketing authorisation or accept an application to extend an existing marketing authorisation, for the same therapeutic indication, in respect of a similar medicinal product.

Article 3 of Commission Regulation (EC) No 847/2000 defines a similar medicinal product as a medicinal product containing a similar active substance or substances as contained in a currently authorised orphan medicinal product, which is intended for the same therapeutic indication.

It also defines similar active substance as an identical active substance, or an active substance with the same principal molecular structural features (but not necessarily all of the same molecular features) and which acts via the same mechanism.

Based on the abovementioned definitions, the assessment of similarity between two medicinal products takes into consideration the following criteria:

  • principal molecular structural features;
  • mechanism of action;
  • therapeutic indication.

If significant differences exist within one or more of these criteria, the two products will not be considered as similar. These criteria are explained in the guideline on aspects of the application of Article 8(1) and 8(3) of Regulation (EC) No 141/2000.

If your product is considered to be similar to any authorised orphan medicinal product, you will have to provide justification in module 1.7.2 that one of the following derogations, laid down in Article 8(3) of the Orphan Regulation applies:

  • the holder of the marketing authorisation for the orphan medicinal product has given its consent for submission of your application, in which case a signed letter from the marketing-authorisation holder of the orphan medicinal product should be provided confirming the consent for submission of an application for marketing authorisation;
  • the holder of the marketing authorisation for the orphan medicinal product is unable to supply sufficient quantities of the medicinal product, in which case the applicant should provide a report including details of the supply shortage and justify that patients’ needs in the orphan indication are not being met;
  • the applicant can establish that its product, although similar to the orphan medicinal product already authorised, is more effective, safer or otherwise clinically superior, in which case a critical report justifying clinical superiority to the authorised product must be provided.

For information on the procedure and timetable for assessment of similarity and, where applicable, a derogation report vis-à-vis authorised orphan medicinal products, please refer to the question what is the procedure and timetable for assessment of similarity and, where applicable, derogation report vis-à-vis authorised orphan medicinal products?

Please note that if the Agency identifies a possible similarity issue not addressed by the applicant before validation, the applicant will be asked to complete the application with information on similarity and, if applicable, on one of the derogations. Validation of the application will only proceed once the applicant has submitted either a report justifying the lack of similarity or, if similar, additional information justifying one of the derogations in Article 8(3).

As considerable time may elapse between validation of an application and adoption of an opinion, if applicants become aware of medicinal products that have been authorised as orphans for a condition related to the therapeutic indication proposed in your application, this information should be communicated promptly to the product team leader at the Agency in order to arrange for the submission of updated application form and modules 1.7.1 and 1.7.2, as applicable.

In any case, the Agency will check whether new orphan medicinal products have been authorised for the same condition at certain milestones of the procedure, i.e. at day 120, day 180 and prior to adoption of an opinion from the Committee for Medicinal Products for Human Use (CHMP).

Please note that applicants are not expected to submit a similarity report against their reference medicinal product, since a generic or hybrid application can only be submitted once the period of market exclusivity of the reference medicinal product has expired, unless justification is provided to support one of the derogations laid down in Article 8(3) of the Orphan Regulation.

Generic medicinal products are, by definition, considered similar to the reference medicinal product and, therefore, the therapeutic indications for the reference medicinal product which benefit from a separate period of market exclusivity cannot be included in the proposed product information for the generic medicinal product, unless justification is provided to support one of the derogations laid down in Article 8(3) of the Orphan Regulation.

References

15. Can I submit my generic or hybrid 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 to new uses of the medicine, such as new indications and pharmaceutical forms. While this 'usage-patent' protection is in place, a generic or hybrid medicine cannot be marketed for the protected indication or pharmaceutical form, even if the period of data and market exclusivity of the reference medicine has expired.

Applications for marketing authorisation for generic or hybrid 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 (EC) No 726/2004 allow applicants and marketing-authorisation holders to exclude those parts of the summary of product characteristics of the reference medicinal product referring to indications or dosage forms still covered by patent law from their proposed product information.

References

16. If the patent situation differs in the various Member States, how will this be reflected in the product information of my generic or hybrid 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 generic and hybrid access to the centralised procedure, 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 or 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 summaries of product characteritstics, the applicant should commit, as part of the marketing-authorisation application, to extend the indications or pharmaceutical forms of the duplicate marketing authorisation as soon as the patent restrictions no longer exist, or it should commit to withdrawing the marketing authorisation with restricted indications or pharmaceutical forms when the relevant patents are no longer in force.

Multiple marketing-authorisation applications and post-authorisation activities for generic or hybrid medicinal products, justified on the basis of existing patent protection for the reference medicinal product, are eligible to fee incentives. See the "Explanatory note on fees payable to the European Medicines Agency".

References

 

17. If a therapeutic indication is covered by patent law, which sections of the summary of product characteristics 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 of 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 summary of product characteristics should be maintained.

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

18. How can I update the product information of my generic or hybrid 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 generic or hybrid medicinal product with the product information of the reference medicinal product following expiry of the patent.

References

19. When should I submit mock-ups and specimens?

See presubmission guidance: questions 11-20.

20. Do I have to submit samples together with my application?

See presubmission guidance: questions 11-20.

21. Am I, as applicant, duly established in the European Economic Area?

See presubmission guidance: questions 21-30.

22. What information relating to manufacture and batch release should be provided as part of my application? Is it possible to add, replace or remove manufacturing sites during the evaluation process?

See presubmission guidance: questions 21-30.

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