7. Types of Marketing Authorisation Applications

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1. 7 Types of Marketing Authorisation Applications

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There is not simply one type of marketing authorisation application in Europe, the list below shows what types of application are available. 

Types of applications for a Marketing Authorisation of a medicine

  • Full (Stand-alone) application
  • Generic application
  • Hybrid application
  • Similar biological product (biosimilar) application
  • Well established use application
  • Fixed combination application
  • Informed consent’ application
  • Mixed application

Legal basis: Articles 8(3) and 10, 10a, 10b, or 10c of Directive 2001/83 (EC) and Article 6 of Regulation (EC) 726/2004

1.1. Full (Stand-alone) application

For full applications the results of pharmaceutical tests (physico-chemical, biological or microbiological), pre-clinical tests (pharmacological and toxicological), and clinical trials need to be submitted. Detailed data requirements are set-out in Annex I to Directive 2001/83/EC, as amended by Commission Directive 2003/63/EC.
(all CTD Modules as described above in detail).

Legal basis: Article 8(3) of Directive 2001/83 (EC)

1.2. Generic application

The applicant for an MA is not required to provide the results of non-clinical tests and clinical trials if the applicant can demonstrate that the medicine is a generic medicine of a reference medicine which is or has been authorised under Article 6 of Directive 2001/83/EC for not less than 8 years in a Member State or in the Union.

A generic medicine is defined as having:

This type of application refers to information contained in the dossier of the authorisation of the reference medicine. A marketing authorisation for the reference medicine has been granted on the basis of a complete dossier in accordance with article 8(3), 10a, 10b or 10c of Directive 2001/83/EC.

Legal Basis: Article 10 (1,2) of Directive 2001/83 (EC)

1.3. Hybrid application

A hybrid application differs in certain cases, where results of non-clinical tests or clinical trials are required. These applications rely in part on the results of non-clinical tests and clinical trials for a reference product, and partly on new data.

This is necessary in three cases:

At the time of submission of a generic/hybrid application, the period of data exclusivity* of the reference medicine must have expired in order to allow the applicant to rely on the dossier of the reference medicine. Data exclusivity is not less than eight years after authorisation in the EU.

In addition, an authorised generic medicine shall not be placed on the market until ten years after the initial authorisation of the reference product. The period of ten years from initial authorisation of the reference product provides a period of market protection** for the reference product.

* This period provides a time of so-called “data exclusivity” to the reference product, which means that eight years from the initial authorisation of a medicine the marketing-authorisation holder benefits from the exclusive rights to the results of preclinical tests and clinical trials on the medicine. After this period, the marketing authorisation holder is obliged to release this information to companies wishing to develop generic versions of the medicine.

** The protection of an approved medicine against competition from generic medicines that extends beyond the protection conferred by data exclusivity. During this period, applications for generics can be accepted and authorised, but the generic medicines cannot be placed on the market.

Legal basis: Article 10 (3) of Directive 2001/83 (EC) and Article 6 of Regulation (EC) 726/2004

1.4. Biosimilars application

A biosimilar is a biological medicine highly similar to another biological medicine already approved in the EU, the reference medicine. Similarity refers to structure, biological activity and efficacy, safety and immunogenicity profile (the intrinsic ability of proteins and other biological medicines to cause an immune response).

A biosimilar is not regarded as a generic of a biological medicine. This is mostly because the natural variability and more complex manufacturing of biological medicines do not allow an exact replication of the molecular micro-heterogeneity. In this way they are not identical. Consequently, more studies are required for regulatory approval of biosimilars than for generics. Comprehensive comparability studies are needed to generate evidence substantiating the similar nature, in terms of quality, safety and efficacy (absence of clinically meaningful differences), of the similar biological medicine and the chosen reference medicinal product.

Legislation states: Where a biological medicine which is similar to a reference biological product does not meet the conditions of a generic product, the results of appropriate non-clinical tests or clinical trials must be provided. This applies in particular to differences relating to:

  • raw materials (e.g., difficulty to characterise, such as biological substances arising from extraction from biological sources).
  • manufacturing processes.

The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Section 4, Part II, Annex I to Directive 2001/83/EC and the related detailed guidelines. Due to the diversity of biological medicines the need for additional non-clinical tests and clinical studies will be identified by the competent authorities. The chosen reference medicine must be a medicine authorised in the Union, on the basis of a complete dossier in accordance with Article 8 of Directive 2001/83/EC.

Legal basis: Article 10 (4) of Directive 2001/83 (EC); Annex I, Part II section 4 of Directive 2001/83/EC

1.5. Well-established use application

Results of non-clinical tests and/or clinical trials are not required if the applicant can demonstrate that the active substances of the medicine have been in well-established medicinal use for at least ten years in the EU, with accepted efficacy and an acceptable level of safety. Results of non-clinical tests and/or clinical trials have to be replaced by detailed reference to appropriate scientific literature (information available in the public domain).

For such applications, Modules 1, 2 and 3 should be submitted following the provisions in Annex I to Directive 2001/83/EC. For Modules 4 and 5, a detailed scientific bibliography shall address all required non-clinical and clinical characteristics, and should be summarised in Module 2. They are considered as full and independent applications. If parts of the dossier are incomplete, such absences in the non-clinical/clinical overviews must be justified, as with any other full application.

Criteria to consider for well-established use:

  • the time over which a substance has been used with regular application in patients;
  • quantitative aspects of the use of the substance;
  • the extent of use on a geographical basis;
  • the extent to which the use of the substance has been monitored by pharmacovigilance or other methods;
  • the degree of scientific interest in the use of the substance (reflected in the published scientific literature) and the coherence of scientific assessments;

Legal basis: Article 10a of Directive 2001/83 (EC)

1.6. Fixed combination application

The combination of active substances within a single pharmaceutical form of administration according to the legal basis is a so-called 'fixed combination'.

For medicines containing active substances used in already authorised products but not yet used in combination, the results of new non-clinical tests or new clinical trials relating to that combination have to be provided. However, it is not  necessary to provide scientific references relating to each individual active substance.

A full dossier, comprising all the information of modules 1 to 5, has to be provided for the fixed combination. Any absence of specific fixed combination data should be justified in the non-clinical and/or clinical Overviews. It is possible to include information on the individual substances (literature or actual data), especially in order to justify the absence of certain specific data on the combination.

Legal basis: Article 10b of Directive 2001/83 (EC)

1.7. Informed consent application

The marketing authorisation application for a product  is called an ‘informed consent application’, if it possesses the same qualitative and quantitative composition in terms of active substance(s) and the same pharmaceutical form as a reference product already authorised, using that dossier. For such application it is a prerequisite that consent has been obtained from the marketing authorisation holder of the reference product for all three modules containing the pharmaceutical, pre-clinical and clinical data (modules 3, 4 and 5). Permanent access to this documentation or possession of the information should be ensured.

For the informed consent application, only a complete module 1 should be submitted, including the eApplication Form with relevant Annexes and the letter of consent from the MAH of the authorised medicine allowing access to modules 2, 3, 4, 5 of the initial dossier and any subsequent documentation submitted.

Of note: Despite the fact that the provision contains some criteria that are common to the definition of a generic medicine in Article 10, Article 10c does not concern generic medicines.

Legal basis: Article 10c of Directive 2001/83 (EC)

1.8. Mixed Application

Where module 4 (safety - non-clinical tests) and/or module 5 (efficacy - clinical studies) of the application consist of a combination of reports of limited non-clinical tests and/or clinical studies carried out by the applicant and of bibliographical references*.

All other Module(s) are in accordance with the structure of the Full dossier (this can also be called ‘Full mixed application’). A justification should be given for providing literature references instead of results of certain tests/trials, and why the references can replace study reports, and how the results presented fulfil the requirements as set out in the Annex I to Directive 2001/83/EC. The competent authority shall accept the proposed format on a case-by-case basis.

Legal basis: Annex I Part II section 7 of Directive 2001/83 (EC):

* Bibliographical references: published pharmaco-toxicological information including scientifically accepted monographs and clinical trials, as well as results of post marketing experience gained by widespread clinical use in humans.

1.9. Continuous update of marketing authorisations

Marketing authorisations for medicines are dynamic and not static, and the dossier underlying a marketing authorisation must be regularly updated. This ensures that scientific progress and new regulatory requirements are respected, in accordance with Article 23 of Directive 2001/83/EC, Annex I to Directive 2001/83/EC and Article 16 of Regulation (EC) No 726/2004.

Specifically, any information which may influence the evaluation of the benefits and the risks of the medicine must be promptly supplied. In this regard, marketing authorisation holders of marketing authorisations granted in accordance with Article 10 or 10c of Directive 2001/83/EC should implement variations swiftly whenever the marketing authorisation of the reference medicine is changed to address a safety or efficacy concern. In addition, the marketing authorisation holder should inform the competent authorities relating to any pharmacovigilance concerns according to Article 104 of Directive 2001/83/EC.