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Regulatory Pathways in the EU - overview

Prior to initiating a drug development program there are certain questions and considerations that should be answered with the main aim to create a robust set of data that will convince regulators that the drug demonstrated a favorable benefit-risk profile and can ultimately be placed on the market in the EU.

These questions and consideration will be developed over a series of senior management meetings including the input from the non-clinical, clinical, quality (CMC), regulatory, finance, legal, QA experts.

Usually, the initial ideal regulatory pathway will be pursued and in the discussion with the EMA and National regulatory bodies, it will be further refined and amended.

Legal Basis of the Application in the EU

The drug development program will largely depend on the proposed type of the Marketing Authorization Application (MAA). It is of the utmost importance to discuss the proposed MAA with the concerned regulatory agency in advance.

Overview of the Regulatory pathways

Article 8(3) Full or full-mixed application

Full: For this type of application the results of pharmaceutical (physico-chemical,

biological or microbiological) tests, non-clinical (toxicological and pharmacological) tests and clinical trials should be submitted. All submitted documentation is expected to be in accordance with the Annex I of the Directive 2001/83/EC.

Full-Mixed: marketing-authorisation application dossiers where Module 4 and/or 5 consists of a combination of reports of limited non-clinical and/or clinical studies carried out by the applicant and of bibliographical references

Article 10: Abridged applications (generic, hybrid, biosimilar)

Abridged applications include derogation from the requirements for a full marketing authorization. The development will be conducted versus a reference medicinal product which was authorized in the EU based on full dossier i.e. Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC.

Submission is only possible once data protection period of reference medicinal product has expired.


- same active substance

- same strength

- same pharmaceutical form,

- bioequivalence has been demonstrated by appropriate bioavailability studies

- additional clinical trials not needed, additional non-clinical tests not needed

- biowaiver may be possible (i.e. no need for BE studies) in certain cases

- immediate-release oral pharmaceutical forms (tablets, capsules, oral solutions, and suspensions) are considered to be one and the same pharmaceutical form

- The SmPC should in all relevant respects be consistent with that of the reference medicinal product (except for patent/SPC protected indications and dosage forms).


Hybrid medicines are medicines whose authorisation depends partly on the results of tests on the reference medicine and partly on new data from clinical trials.

This happens when a manufacturer develops a generic medicine that is based on a reference medicine, but has a different strength, a different route of administration or a slightly different indication from the reference medicine.

- the strict definition of a generic medicinal product is not met,

- bioequivalence cannot be demonstrated through bioavailability studies

- in case of changes in active substance(s), therapeutic indications, strength, pharmaceutical form, or route of administration compared to the reference medicinal product.

Applicant’s own clinical and non-clinical studies + dossier of the Reference Medicinal Product


A biological medicine highly similar to another already approved biological medicine in the European Union (EU), for which marketing exclusivity rights have expired.

Biosimilar is similar to a reference biological product, but do 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.

Sponsors are required to demonstrate through comprehensive comparability studies:

- their biological medicine is highly similar to the reference medicine, notwithstanding natural variability inherent to all biological medicines;

- there are no clinically meaningful differences between the biosimilar and the reference medicine in terms of safety, quality and efficacy.

Comparability is conceived as a step-wise process that is tailor-made for each product

EMA offers a tailored scientific advice to support the development of new biosimilars.

The tailored procedure advises developers on the studies they should conduct, based on a review of the quality, analytical and functional data they already have available.

Article 10a: Well-Established Use Application

Application for marketing authorisation may be based on results from the scientific literature when:

- an active ingredient of a medicine has been used for more than 10 years and

- its efficacy and safety have been well established - in terms of the conditions set

out in Annex I.

Safety and efficacy need to be demonstrated by published scientific literature (i.e. available in public domain, published by reputable source/peer-reviewed). Assessment reports (e.g. EPARs) not acceptable for this purpose. Studies may be provided only for bridging to support relevance of the literature.

Article 10b: Fixed Combination Application

- authorised medicinal products but not hitherto used in combination for therapeutic purpose

- individual substances must have been authorised in the EU

- the results of new pre-clinical tests or new clinical trials relating to that combination should be provided – i.e. own non-clinical/ clinical data on the combination is needed

- it shall not be necessary to provide scientific references relating to each individual active substance - Derogation from the requirement of providing data on individual


Article 10c: Informed Consent Application

Allows applicant to use quality, non-clinical and clinical documentation of an already approved medicine, for the purpose of a subsequent application. Marketing Authorisation Holder of the reference product needs to give their consent (Letter of Consent) confirming permanent access to data.

Both medicines must have: the same qualitative and quantitative composition in terms of active substance(s), and the same pharmaceutical form.

Non-Standard Marketing Authorisations

Conditional Marketing Authorisation

In the interest of public health, applicants may be granted a conditional marketing authorisation for such medicines on less comprehensive clinical data than normally required.

The available data must indicate that the medicine’s benefits outweigh its risks and the applicant should be in a position to provide the comprehensive clinical data in the future.

Conditional marketing authorisations are valid for one year and can be renewed annually.

Once a conditional marketing authorisation has been granted, the marketing authorisation holder must fulfil specific obligations within defined timelines.

During the COVID-19 pandemic, the conditional marketing authorisation procedure is being used to expedite the approval of safe and effective COVID-19 treatments and vaccines in the EU.

Marketing Authorisation under Exceptional Circumstances

The applicant is unable to provide comprehensive data on the efficacy and safety under normal conditions of use, because:

- the condition to be treated is rare or

- because collection of full information is not possible

- or is unethical.

MA is a subject to specific obligations (SOBs), in particular relating to safety.

Standard validity of MA (5 years): Annual re-assessment of benefit/risk based on progress of SOBs.

It is important to highlight that there are several Marketing Authorisation Application procedures in the EU, that require detailed breakdown and will only be briefly mentioned here:

- Centarlised Procedure

- Decentralized Procedure

- Mutual Recognition Procedure

- National Procedure

Under the centralised authorisation procedure, pharmaceutical companies submit a single marketing-authorisation application to EMA, to market the medicine and make it available to patients and healthcare professionals throughout the EU on the basis of a single marketing authorisation.

The centralized procedure is compulsory for human medicines containing a new active substance to treat: HIV, cancer, diabetes, neurodegenerative diseases, auto-immune and other immune disfunctions, viral diseases, medicines derived from biotechnology, ATMP, orphan diseases. It is optional for other medicines.

EMA's Committee for Medicinal products for Human Use (CHMP) carry out a scientific assessment of the application and give a recommendation on whether the medicine should be marketed or not. CHMP should deliver its opinion within 210 days.

The European Commission is the authorising body for all centrally authorised product, who takes a legally binding decision based on EMA's recommendation. This decision is issued within 67 days of receipt of EMA’s recommendation.

The centralised marketing authorisation is valid in all EU Member States as well as in the European Economic Area (EEA).

If a company wishes to request marketing authorisation in several EU Member States for a medicine that is outside the scope of the centralised procedure, it may use one of the following routes:

- mutual-recognition procedure, whereby a marketing authorisation granted in one Member State can be recognised in other EU countries;

- decentralised procedure, whereby a medicine that has not yet been authorised in the EU can be simultaneously authorised in several EU Member States.


While the majority of new, innovative medicines are evaluated by EMA and authorised by the European Commission in order to be marketed in the EU, most generic medicines and medicines available without a prescription are assessed and authorised at national level in the EU. Information about national procedures can be found on the websites of national competent authorities.

Possible MAA outcomes are:

- Positive

- Negative/unfavorable CHMP opinion

- Conditional opinion

Some useful points to consider when deciding on the regulatory pathway in the EU:

- Discuss early within company what type of data will be needed for the MAA. Discuss with the concerned competent authority(ies) in advance the legal basis for the MAA. Will the full set of quality, clinical and non-clinical data (studies) be needed?

- Will the medicine potentially be used to treat children? Is the drug an orphan drug?

- What procedure will be used i.e. central, national, MRP, DCP?

- Are the any incentives/designations/programs that can speed up the development program?

- What types of meetings with the competent authorities will be sought?

- What are the foreseen timelines until the positive opinion is granted ?


1 comentario

6 days ago

Very informative! What are the supportive document/data requirements for the submission of a generic dossier where the API is a well established use API? Must comparative dissolution data between the generic and the original product be generated in support of a biowaiver?

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