Presubmission guidance: questions 45 to 56

  • Email
  • Help

This page lists questions 45 to 56 of the European Medicines Agency's questions and answers on presubmission guidance.

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.

Jump to other questions

Back to top

45. What is the period of protection for my medicinal product? New July 2006

Data-exclusivity and market-exclusivity period for reference medicinal products

A reference medicinal product is a medicinal product that has been granted a marketing authorisation by a Member State or by the European Commission on the basis of a complete dossier, i.e. with the submission of quality, preclinical and clinical data in accordance with Articles 8(3), 10a, 10b or 10c of Directive 2001/83/EC, as amended, and to which the marketing-authorisation application for a generic, hybrid or similar biological medicinal product (i.e. application under Articles 10(1), 10(3) or 10(4) of the same Directive) refers.

Also see 'what will be the legal basis for my application?' in presubmission guidance: questions 1 to 10.

Submission of the marketing-authorisation application (MAA) before 20 November 2005: previous periods of protection

Reference medicinal products authorised through the centralised procedure for which the initial submission was made before 20 November 2005 continue to benefit from the previous periods of protection, which are 10 years, (and 10 years for all medicinal products authorised following an opinion of the Committee for Medicinal Products for Human Use (CHMP) in accordance with Article 4 of Directive 87/22/EEC (ex-concertation procedure)).

According to Article 89 of Regulation (EC) No 726/2004, the new periods of protection do not apply to those reference medicinal products for which the initial application for authorisation (date of submission of the application and not validation) was submitted before 20 November 2005.

Notion of global marketing authorisation: Particular case of fixed combinations

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 procedures and under a different name, granted to the marketing-authorisation holder of the initial authorisation.

In accordance with Article 6(1) of Directive 2001/83/EC, as amended, all the presentations of a given product shall be considered as part of the same marketing authorisation for the purposes of applying the rules on data and marketing protection.

This means that for a reference medicinal product, the start of the data-and market-exclusivity periods is the date when the first marketing authorisation was granted in the Community. New additional strengths, pharmaceutical forms, administration routes or presentations, as well as any variations or extensions do not restart or prolong this period. This will apply even if the new presentation has been authorised to the same marketing-authorisation holder through a separate procedure and under a different name.

Fixed combinations are not considered part of the global marketing authorisation and will beneficiate from an independent period of protection.

Submission of the MAA after 20 November 2005: new periods of protection

Directive 2001/83/EC, as amended, and Regulation (EC) No 726/2004 have introduced new rules concerning the periods from the initial marketing authorisation of the reference product, during which generic-, hybrid- or similar-biological-medicinal-product applicants cannot rely on the dossier of the reference product for the purposes of submitting an application, obtaining a marketing authorisation or placing the product on the market.

Applications for generic, hybrid or similar biological medicinal products can be submitted after a so-called data-exclusivity period of eight years from initial authorisation of the reference medicinal product. Generic, hybrid or similar biological medicinal products authorised in this way can be placed on the market after a so-called market-exclusivity period of 10 years from initial authorisation of the reference medicinal product.

One year period of protection for new indications for well established substances

According to Article 10(5) of Directive 2001/83/EC as amended, 'where an application is made for a new indication for a well established substance, a non-cumulative period of one year of data exclusivity shall be granted, provided that significant preclinical or clinical studies were carried out in relation to the new indication.'

The data-exclusivity period refers exclusively to the data concerning the new indications.

Commission decisions authorising new therapeutic indications for well established substances will contain a clear statement of whether the new indication is based on significant preclinical or clinical studies.

A well established substance is an active substance included in the relevant medicinal product which can be shown to have a well established use in accordance with the requirements of indent (a) in section 1 ('well established medicinal use') of part II of the annex to Directive 2001/83/EC as amended. This does not, however, mean that the medicinal product concerned must have been authorised under the legal basis of the well established use procedure.

A new indication submitted after 20 November 2005 may benefit from this year of protection.

One-year period of protection for data supporting a change of classification

According to Article 74a of Directive 2001/83/EC as amended, 'where a change of classification of a medicinal product has been authorised on the basis of significant preclinical tests or clinical trials, the competent authority shall not refer to the results of those tests or trials when examining an application by another applicant for or holder of marketing authorisation for a change of classification of the same substance for one year after the initial change was authorised.'

The one-year period of protection covers significant preclinical or clinical trials carried out for the purpose of substantiating an application for a change of classification. The interpretation by competent authorities of the notion of significant preclinical tests or clinical trials under Article 74a will be without prejudice to the interpretation of that phrase under Article 10(5) of the Directive.

When adopting a decision authorising a change of classification of a medicinal product, the competent authority must assess whether the change is based on significant preclinical tests or clinical trials. In the case of products authorised in accordance with Regulation (EC) No 726/2004, Commission decisions authorising a change of classification will contain a clear statement of whether the change is based on significant preclinical tests or clinical trials.

Also see the guideline on changing the classification for the supply of a medicinal product for human use.

A change of classification authorised after 20 November 2005 may benefit from this year of protection.

Extension of the ten-year period of marketing protection in the case of new therapeutic indications (8+2+1)

In accordance with Article 14(11) of Regulation (EC) No 726/2004, the ten-year period of marketing protection (8+2) may be extended by one year in the event of authorisation of new therapeutic indications, but only if:

  • the new application represents a significant clinical benefit in comparison with existing therapies;
  • the new indication is granted during the first eight years since the initial marketing authorisation.

This additional year of marketing protection applies to the global marketing authorisation for the reference medicinal product. Generic, hybrid or similar biological medicinal products, with or without the new therapeutic indication, may not be placed on the market until expiry of the eleventh year.

The overall period of protection cannot exceed eleven years. Therefore, this provision can be used only once per global marketing authorisation within the meaning of Article 6(1) of Directive 2001/83/EC as amended.

Commission decisions authorising new therapeutic indications will contain a clear statement of whether the new indication represents a significant clinical benefit in comparison with existing therapies.

This year of protection shall apply only to those reference medicinal products for which the initial application for authorisation is submitted after 20 November 2005.

Detailed information on market exclusivity for orphan medicinal products is provided in the communication from the Commission on Regulation (EC) No 141/2000 on orphan medicinal products (section D) and in the guideline on aspects of the application of Article 9(1) and (3) of Regulation (EC) No 141/2000: Assessing similarity of medicinal products versus authorised orphan medicinal products benefiting from market exclusivity and applying derogations from that market exclusivity.


46. How shall I submit my EU Risk Management Plan as part of my Marketing Authorisation Application? Rev. September 2015

1. When should I submit my RMP? Rev. Sep 15

A RMP shall be submitted for all initial marketing authorisations irrespective of its legal basis. However, in certain circumstances, certain parts or modules of the RMP may be omitted, unless otherwise requested by the competent authority. Specific details can be found in Guideline on good pharmacovigilance practices (GVP) Module V – Risk management systems, paragraph V.C.3.1.Applicants are generally encouraged to contact the EMA prior to submitting new applications to discuss RMP related questions.

At any stage, but in particular during the pre-authorisation phase, a MAA/MAH may request advice on the development or content of an EU-RMP through the scientific advice procedure.

Whether or not the scientific advice procedure has been used, discussion on any questions relating to the RMP (safety concerns or pharmacovigilance activities) for a medicinal product seeking a new authorisation through the centralised procedure should take place at the pre-submission meeting.

2. What are the requirements for an RMP for a new application of an established generic product? Rev. Sep 15

Marketing authorisation applications for generic medicinal products under Article 10(1) of Directive 2011/83/EC  should include an RMP in the application dossier. However as outlined in the Good Pharmacovigilance Practice (GVP) module V on risk management systems some parts or modules of the RMP for a generic may be omitted (see GVP V section V.C.3.1).

3. If there is no RMP in place for a reference medicinal product, how should module SVIII ‘summary of the safety concerns’ be populated for a generic medicinal product? Rev. Sep 15

The applicant of the generic medicinal product should use the (European) public assessment and the summary of product characteristics of the reference medicinal product to obtain the safety concerns to be included in module SVIII of the RMP. Applicants may also discuss during the pre-submission phase what safety concerns should be included.

4. Do I need to submit an RMP for my traditional herbal medicinal product?

The submission of an RMP is not required for an application for a traditional–use registration.

For other herbal medicinal products not falling within the scope of the traditional-use registration, an RMP will be required for any initial marketing authorisation applications.

5. When can I submit an RMP within a procedure?

A RMP can be submitted as part of an initial marketing authorisation application. Furthermore, a RMP or RMP update can be submitted as part of a renewal, or a regulatory procedure involving a change to an existing marketing authorisation (e.g. extension of indication, line extension, and new manufacturing process of a biotechnologically-derived product).

Also, if a change to the RMP is necessary based on a safety variation to update the Summary of Product Characteristics, Labelling or Package Leaflet, the RMP can be submitted within that variation procedure.

If final study results are submitted for assessment through a variation, and the finalisation of the study leads to the need to update the RMP, this RMP update can be submitted as part of that variation. However, if interim results of a study lead to the need for an updated RMP (addition/deletion of safety specifications) a stand-alone variation for the RMP update should be submitted.

A RMP update can only be submitted together with a PSUR of a single centrally authorised medicinal product when the changes to the RMP are a direct result of data presented in the PSUR.

As an interim measure, submission of RMP updates cannot be accepted together with the PSURs of medicinal products (centrally and/or nationally authorised) subject to a PSUR EU single assessment (PSUSA). MAHs should update their RMP through another upcoming procedure affecting the RMP or alternatively, through a separate variation which can be submitted after finalisation of the PSUR single assessment procedure.

Any (update of the) RMP provided outside another regulatory procedure should be submitted through a separate stand-alone variation.

6. When is my RMP a stand-alone variation?

If a new/initial RMP is submitted outside of another regulatory procedure, this RMP should be submitted as a stand-alone variation.

A stand-alone variation for updates of the RMP is foreseen when safety concerns are added or deleted outside another procedure. For instance, if interim results of a study lead to the need to add or to delete safety specifications a stand-alone variation for the RMP update should be submitted.

A further submission of an updated RMP as a stand-alone variation is expected when the MAH proposes changes to already previously agreed category 3 studies in Part III.4.3 of the RMP. This also applies when the MAH provides an updated or amended protocol that changes the previously accepted protocol with an impact on part III.4.3.

7. How shall I present my RMP? Rev. Sep 15

Guidance on the format and content of the RMP as outlined in GVP module V and RMP template has been made available in the pharmacovigliance section of the Agency's website. The submitted RMP should follow the RMP template and guidance.

The RMP should be provided in CTD section 1.8.2.

RMP versions submitted for assessment should be version controlled and dated.

All parts and modules of the RMP should be submitted in one single PDF-file so that a complete RMP is provided to the Agency.

8. Should I submit a summary of the RMP and will it be published? Rev. Sep 15

Yes, the summary of the RMP is a mandatory element of any RMP submission and the Agency will make it publicly available.

Guidance on the format and content of the RMP for MAA/MAH, including the RMP summary (Part VI), is available published on the Agency’s website. The applicant/MAH should prepare a summary in Part VI on the RMP which will be assessed as part of the MAA evaluation process and will form the basis for the public RMP summary. 

The RMP summary should be added to any authorised RMP that still does not have a summary, when introducing the new format.

9. Should I provide documents with tracked changes highlighted to facilitate review? Rev. Sep 15

Only clean versions of documents in PDF format should be managed within the eCTD lifecycle.
If additional formats are required by any authority to facilitate the assessment (e.g. tracked changes versions for SmPCs, Risk Management Plans or other documents as specified by the agency), these should be provided in Word format in the separate folder ‘XXXX-working documents’. Further details can be found in section 2.9.9 of the TIGes Harmonised Guidance for eCTD Submissions in the EU.

10. Can more than one draft RMP be submitted for regulatory assessment?

Different sections of the approved version of the RMP can be under review as part of different procedures. Any submitted version of the RMP should be based on the latest approved version and should be seen as a draft, until approved.  Details of the RMP approval status should be provided in the Module I of the document.

In line with current guidance (GVP Module V) an RMP update and submission for regulatory review should only be considered when significant new safety information becomes available, unless otherwise requested. For example, the increasing number of exposed patients post-marketing on its own would not represent significant new information for submission of an updated RMP.

If two or more draft RMPs are under evaluation in the context of overlapping procedures (e.g. an RMP update is submitted before the assessment of the RMP previously submitted in the context of another procedure is concluded), at the opinion of the procedure that is finalised last, the MAH should ensure that the approved RMP version includes all the amendments approved in the draft RMPs previously assessed.

Companies are strongly encouraged to streamline RMP amendments and submissions, in co-operation with the EMA (or Reference Member State for non-CAPs), in order to facilitate RMP assessments throughout the product life-cycle.

11. When should study progress reports be submitted?

The timelines of the progress reports should be pre-specified and indicated in the protocol. These progress reports may include available interim results, but there is no obligation or recommendation to include interim results in PSURs and RMPs unless required as part of an agreed pharmacovigilance plan.

12. How long after the European Commission decision should Annex 1 of the RMP be submitted to EudraVigilance?

There are 30 days to submit the Annex 1 of the RMP to EudraVigilance.

13. Should I include all of my ongoing studies in the RMP?

If any or all of the safety issues are safety concerns in the RMP, then a study should be included in the PhV plan, even if, e.g. it would be an observational study using insurance claims data to characterise safety issues. According to the new format, it should be included in III.1. Safety concerns and overview of planned pharmacovigilance actions and its category should be proposed as III.4.3. Additional pharmacovigilance activities required by the CHMP/PRAC to address specific safety concerns or to measure effectiveness of risk minimisation measures.

In addition, if some particular off-label use is a safety concern – either because it is a contraindication and/or use is likely outside of the approved indication – then studies outside of the target population or with a different dose, investigating the safety concern are appropriate in the pharmacovigilance plan.

Studies in the PIP should not be routinely included in the pharmacovigilance plan but any PIP recommendations for long term follow up of safety or efficacy issues should be specifically discussed in section SVI.6 of the RMP. Where use in children is a safety concern it may be appropriate to include individual activities aimed at providing further safety information in the pharmacovigilance plan. The aim here is to allow the safety concern to be investigated, not to provide studies reflecting the development plan for a paediatric indication.

14. How is the assessment of an educational program as additional risk minimisation handled? Rev. Sep 15

The outlines of the educational program (i.e. the key elements) are part of Annex II.D of the marketing authorisation for centrally authorised medicinal products. Assessment of the educational program incorporating these key elements is done at the Member State level since GVP Module V chapter V.C.7 states that Member States have the responsibility for ensuring that the key elements described in the conditions and/or restrictions are implemented by the marketing authorisation holder in their territory. Further guidance for the implementation of the educational material at national level can be found in GVP Module XVI addendum I – Educational materials.

15. Can the internet be used as additional risk minimisation measure (e.g. website with educational materials or videos)?

Use of websites should not be proposed in the RMP as a means of communicating information on additional risk minimisation measures. Mention of a specific medicinal product on a website is regarded as promotional in some Member States and may not be permissible. However, in some Member States it is possible that use of the internet may be permitted as part of the national communication plan agreed at Member State level.

16. How will my RMP be reviewed Rev. Sep 15

The CHMP and the PRAC will be involved in the RMP assessment. The CHMP will focus its evaluation of the RMP on the safety specifications in light of the assessment made on the quality, safety and efficacy of the product while the PRAC will focus its evaluation on the prospective planning aspects i.e. the pharmacovigilance plan and risk minimisation measures.

The PRAC will first issue a separate assessment before Day 120 and any comments and questions will be integrated in the Day List of Questions and CHMP AR. Thereafter the PRAC assessment will be integrated in a joint CHMP-PRAC assessment report after the day 120 List of questions and also in the third phase of assessment.

See also question ”How shall my procedure be evaluated?”.

17. Can I submit a version of the RMP after the opinion to reflect the last minute changes made during the CHMP?

A tidied version of the RMP which was agreed at the time of the Opinion should be submitted within 15 days of the opinion to facilitate publication of the summary of the RMP and the EPAR.  It is important to make it clear that this is not a new version, but a finalised version of what was agreed at the time of the opinion. Therefore, it will keep the version number of the agreed opinion RMP and have a suffix ‘W’.  It should be submitted via Eudralink and should not contain any new data.

For example:

  • Version 8.0: RMP agreed at the time of the Opinion but requiring slight amendments due to last minute changes agreed at the Opinion
  • Version 8.0(W): word version of amended RMP submitted within 15 days of the opinion
  • Version 8.0: RMP (including amendments) in closing eCTD sequence.


47. Pharmacovigilance system Rev. February 2015

Requirements regarding the summary of the pharmacovigilance system

Applicants for marketing authorisation are required to provide a summary of their pharmacovigilance system, in accordance with Article 8(3)(ia) of Directive 2001/83/EC

which they will introduce once the authorisation is granted.

The requirement for the summary of the pharmacovigilance replaced the previous requirement for the submission of a detailed description of pharmacovigilance system in the application for marketing authorisation.

The summary of the pharmacovigilance system should be provided in Module 1.8.1 of the application for marketing authorisation and includes the following elements:

  • proof that the applicant has at its disposal a qualified person responsible for pharmacovigilance;
  • the Member States in which the qualified person resides and carries out his or her tasks;
  • the contact details of the qualified person;
  • a statement signed by the applicant to the effect that the applicant has the necessary means to fulfil the tasks and responsibilities listed in title IX of Directive 2001/83/EC;
  • a reference to the location where the pharmacovigilance-system master file (PSMF) for the medicinal product is kept.

The applicant may combine this information in one single statement using the required statement as per Article 8(3)(ia) of Directive 2001/83/EC regarding the obligation to have the necessary means to fulfil the tasks and responsibilities listed in Title IX. Such statement should be signed by an individual who can act on behalf of the legal entity of the applicant/MAH and by the qualified person for pharmacovigilance (QPPV). The title, role and responsibility of each individual signing the statement should be clearly specified in the document.

The summary of pharmacovigilance system is specific to each marketing authorisation application as per legislation and therefore should be signed by the relevant applicant/MAH.

Applicants are required to include a summary of their pharmacovigilance system at the time of submission of an initial MAA.

The requirement for the summary of the pharmacovigilance system is the same for any MAA, independent of the legal basis for the application.

Requirements regarding the pharmacovigilance system and PSMF

The MAH has to operate a pharmacovigilance system for the fulfilment of its pharmacovigilance tasks.

The pharmacovigilance-system master file (PSMF) is a detailed description of the pharmacovigilance system used by the MAH with respect to one or more authorised medicinal products.

The PSMF is not part of the marketing-authorisation (MA) dossier and is maintained independently from the MA. It should be permanently available for inspection and should be provided within seven days to the competent authorities if requested. The PSMF must be located either at the site in the European Union (EU) where the main pharmacovigilance activities of the MAH are performed or at the site in the Union where the QPPV operates. The QPPV has to both reside and operate in the EU.

Applicants are required, at the time of initial MAA, to have in place a description of the pharmacovigilance system that records the system that will be in place and functioning at the time of granting of the marketing authorisation and placing of the product on the market. During the evaluation of an MAA, the applicant may be requested to provide a copy of the PSMF for review.

The PSMF has to describe the pharmacovigilance system in place at the current time. Information about elements of the system to be implemented in future may be included, but these should be clearly described as planned rather than established or current.

The pharmacovigilance system will have to be in place and functioning at the time of granting of the marketing authorisation and placing of the product on the market.

Subcontracting pharmacovigilance activities

The MAH may subcontract certain activities of the pharmacovigilance system to third parties. It will nevertheless retain full responsibility for the completeness and accuracy of the PSMF.

The MAH will have to draw up a list of its existing subcontracts between itself and the third parties, specifying the products and territories concerned.

When delegating any activities concerning the pharmacovigilance system and its master file, the MAH retains ultimate responsibility for the pharmacovigilance system, submission of information about the PSMF's location, maintenance of the PSMF and its provision to competent authorities upon request. Detailed written agreements describing the roles and responsibilities for the PSMF's content, submissions and management, as well as to govern the conduct of pharmacovigilance in accordance with the legal requirements, should be in place.

For more guidance on the requirements for pharmacovigilance system and PSMF, please refer to the relevant modules of the guideline on good pharmacovigilance practices.

PSMF number

Applicants are encouraged to request a PSMF number (MFL EVCODE) in advance of the MAA.

If available, the PSMF number (MFL EVCODE) assigned by the extended EudraVigilance Medicinal Product Dictionary (XEVMPD) should be included in the statement in module 1.8.1. However, this information is not part of the compulsory elements as per Article 8(3)(ia) of Directive 2001/3/EC.

For more information on how to obtain a PSMF number, please refer to the documents for electronic submission of information on medicines.


48. What is the CHMP peer review? Rev. February 2015

Peer review is a process by which other members of the CHMP review the (co-)rapporteurs' scientific evaluation, as well as the validity of the scientific and regulatory conclusions reached. It applies during the initial phase of the assessment of a new MAA.

Peer review is part of a quality-assurance system established at CHMP level. It consists of the review of the (co-)rapporteurs' assessment reports for the purpose of improving the quality of the day-120 list of questions by the CHMP members that are assigned by the committee as peer reviewers. It is also the particular task of those members assigned as peer reviewers to judge the quality of the assessment reports from (co-)rapporteurs especially in relation to potential divergencies in scientific assessment made by (co-)rapporteurs.

A strengthened peer-review system that can improve the consistency of scientific assessments is one of the objectives set out in the European Medicines Agency road map to 2015.

On appointment of (co-)rapporteurs during a CHMP meeting, the Committee also appoints peer reviewers. The peer reviewers are appointed from amongst the members of the CHMP (including co-opted members) or CHMP alternate members and are identified after having put their names forward on a nomination form (nomination form for rapporteurs). The Committee also decides on the scope of the peer review (modules 3, 4 or 5) and the number of peer reviewers to be assigned to this task.

On day 112 of the procedure, a dialogue (e.g. teleconference) is set up between the (co-)rapporteurs, peer reviewers and Agency staff to discuss and critically analyse the different objections and concerns raised in the (co-)rapporteur’s overview and draft list of questions.

Peer reviewers' comments are not made available to applicants. Moreover, it is not intended that applicants directly contact peer reviewers or other CHMP members in the context of an ongoing CHMP assessment of an MAA.


49. How can I request a meeting with the Rapporteurs to clarify the questions posed by the Committee? NEW May 2015

After the receipt of the adopted List of Questions or List of Outstanding Issuesand prior to the formal submission of the responses, the applicant can request a clarification meeting with the (Co-) Rapporteurs (from CHMP, PRAC and/or CAT, as relevant) and the EMA (EMA Product Lead and other relevant team members as appropriate). The aim of these meetings is to provide clarifications and guidance to the applicant on the rationale for the Major Objections and/or other issues and to discuss with the Applicants their response strategy and potential need to adjust the response timelines. Such meetings are intended to avoid the submission of inadequate, incomplete or premature responses potentially leading to prolongation of the procedure. It should be emphasised that these meetings are not intended to provide a pre-assessment of the intended responses. These meetings will usually take place via teleconference.

Applicants are advised to refer to “Guidance on meetings with applicants on the responses to questions received from EMA Scientific Committees during the evaluation within the centralised procedure” for further guidance.


50. What is an oral explanation and how is it conducted? NEW May 2015

An oral explanation can be requested either by the applicant or by the relevant EMA committee – the CHMP, CAT (for advanced therapy medicinal products) or, exceptionally, PRAC. Oral explanations are intended to give opportunity to the applicant to explain their position and arguments. They are usually organised when still at Day 180 of the procedure there are major objections concerning the application, which would prevent the Committee from adopting a positive Opinion on the application. It is important that applicants preparing for an oral explanation bear in mind that they are held to only allow clarification of the aspects relating to the outstanding issues.

When the applicant wishes to have the opportunity of an oral explanation, they should present a written request to the relevant committee preferably one month before the anticipated date of the oral explanation and in all cases prior to Day 180. Such request should be sent to the EMA Procedure Manager.

Applicants are advised to refer to “Guidance to applicants / Marketing Authorisation holders on oral explanations at EMA” for practical guidance on preparation for and conduct of oral explanations. Applicants are also reminded that oral explanations are only held in English.



51. Where can I find the relevant documents regarding the pharmaceutical legislation? Rev. March 2013

The treaties on which the European Union and the European Communities are founded are available. To exercise the Union’s competences, the institutions may adopt regulations, directives, decisions, recommendations and opinions.

Information about the hierarchy of the European Union texts can be found in annex I to volume 2A: Procedures for marketing authorisation: Chapter 1: Marketing authorisation.

The rules governing medicinal products in the European Union concerning medicinal products for human use is published on the European Commission website:

  • Volume 1 – Pharmaceutical legislation, contains most of the relevant Directives, Regulations, decisions and communications;
  • Volume 2 – Notice to applicants:
    • Volume 2A - Procedures for marketing authorisation:
      • Introduction;
      • Chapter 1 – Marketing authorisation;
      • Chapter 2 – Mutual recognition;
      • Chapter 3 – Community referral;
      • Chapter 4 – Centralised procedure;
      • Chapter 5 – Variations;
      • Chapter 6 – Community marketing authorisation;
    • Volume 2B - Presentation and content of the dossier: provides guidance for the compilation of dossiers for applications for marketing authorisation, and is applicable for the centralised procedure and national procedures, including mutual-recognition and decentralised procedures;
    • Volume 2C - Regulatory guidelines: related to procedural and regulatory requirements, e.g. renewal procedures, variation procedures, summary of product characteristics (SmPC), package information and classification for the supply, readability of the label and package-leaflet requirements;
  • Volume 3 – Scientific guideline;
  • Volume 4 – Good manufacturing practices;
  • Volumes 5 to 8 apply only to veterinary medicinal products;
  • Volume 9 – Pharmacovigilance: With the application of the new pharmacovigilance legislation as from July 2012, volume 9A is replaced by the good pharmacovigilance practice. However, until the availability of the respective GVP modules, volume 9A remains the reference. GVP modules refer to the Commission Implementing Regulation No 520/2012 of 19 June 2012 on the performance of pharmacovigilance activities. This is a legally binding act published by the European Commission in June 2012 that provides details on the operational aspects for the new legislation;
  • Volume 10 – Clinical trials.

The European Commission website offers the possibility to create a CD-ROM with the content of the rules governing medicinal products in the European Union, which can be used off-line with an integrated search engine.

Scientific guidelines related to quality, safety and efficacy are available, together with concept papers, draft guidelines and overviews of comments received during the consultation on draft versions.

The Agency also publishes procedural and technical guidance and document templates, which are intended to provide technical and procedural advice to applicants for marketing authorisations for medicinal products coming within the scope of the centralised procedure, in particular:


52. Which European Directorate for the Quality of Medicines and Healthcare (EDQM) activities impact on the centralised procedure? Rev. July 2010

The European Directorate for the Quality of Medicines and Healthcare (EDQM) is a directorate of the Council of Europe. It was created in 1996.

The mission of the EDQM is to contribute to the basic human right of access to good-quality medicines and healthcare, and to promote and protect human and animal health by:

  • establishing and providing official standards for the manufacture and quality-control of medicines applicable in all the signatory states of the Convention for the Elaboration of a European Pharmacopoeia;
  • performing the evaluation of applications for certificates of suitability of the monographs of the European Pharmacopoeia (CEPs) and related coordination of related inspections;
  • establishing the list of standard terms, which cover pharmaceutical forms, routes of administration and containers used for medicinal products for human and veterinary use;
  • coordinating activities performed by the official-medicines-control-laboratory network including the annual sampling and testing programme for centrally authorised products (CAPs) within the setting of a network;
  • coordinating activities for the elaboration of programmes and policies linking the quality of medicines to the quality and safety of their use, in the fields of pharmaceutical practice and care, risk prevention and management as regards counterfeiting of medicines, and the classification of medicines as regards their supply;
  • publishing and distributing all EDQM publications, including the European Pharmacopoeia.

EDQM representatives participate as observers to the Agency’s Quality Working Party (QWP) and Biologics Working Party (BWP) meetings, Good Manufacturing Practice (GMP) Inspection Services Group meetings and Committee on Herbal Medicinal Products (HMPC) meetings at the Agency.

European Pharmacopoeia and its use for an application

Pharmacopoeias are collections of standardised specifications, so called monographs, which define the quality reference for pharmaceuticals.

Directive 2001/83/EC on medicines for human use refers to the mandatory character of European Pharmacopoeia monographs in the preparation of dossiers for MAAs.

The texts of the European Pharmacopoeia cover active substances, excipients, substances or preparations for pharmaceutical use of chemical, animal, human or herbal origin, homoeopathic preparations and homoeopathic stocks, antibiotics, dosage forms and containers. The texts of the European Pharmacopoeia also apply to biologicals, blood and plasma derivatives, vaccines and radiopharmaceutical preparations.

The QWP and BWP are consulted during the preparation and the revision of monographs.

Additionally, chemical and biological reference material of the European Pharmacopoeia (chemical and biological reference preparations) to be used where relevant as reference standards for the quality-control of medicinal products and their constituents are adopted by the European Pharmacopoeia and centrally supplied from the EDQM.

With respect to the quality part (chemical, pharmaceutical and biological) of the dossier, all monographs including general monographs and general chapters of the European Pharmacopoeia are applicable.

When test procedures and methods used for manufacturing and controlling the raw materials and active substances or the starting materials, excipients or finished medicinal products are described in the European Pharmacopoeia, the required description to be included in module 3 should be replaced by the appropriate detailed reference to the monographs and general chapters.

What is the scope of the certification procedure of the EDQM?

The certification procedure is intended for substances for which a monograph (general monograph or specific monograph) has been adopted by the European Pharmacopoeia Commission. The procedure does not apply for direct gene products (proteins), products obtained from human tissues, vaccines and blood products and preparations.

Under the official procedure described in Resolution AP-CSP (07) 1 (adopted by the Public Health Committee (Partial Agreement), Council of Europe) and Directive 2001/83/EC and 2003/63/EC, as amended, of the European Union, manufacturers or suppliers of active substances or excipients (organic or inorganic, obtained by synthesis, extraction or fermentation), any product with transmissible-spongiform-encephalopathy (TSE) risk, or herbal products used in the production or preparation of pharmaceutical products can apply for a certificate of suitability (CEP) concerning:

  • the evaluation of the suitability of the monograph for the control of the chemical purity and microbiological quality of their substance according to the corresponding specific monograph;
  • the evaluation of the reduction of transmission-spongiform-encephalopathy (TSE) risk, according to the general monograph;
  • both of the above;
  • the evaluation of the suitability of the monograph for the control of herbal drugs and herbal-drug preparations.

A CEP can be used by the manufacturers of pharmaceutical products in their MAAs to demonstrate the compliance of the substance used with the monographs of the European Pharmacopoeia as referred in Directive 2001/83/EC, as amended. As a result, applicants are exempted of providing the concerned data in the relevant parts of module 3 of the MAA, as they are deemed to be replaced by the CEP, except for some parts needed for the assessment of the medicinal product. For instance, in case of sterile substances, the applicant has to resubmit the data on the sterilisation of the substance to national competent authorities or the Agency. Additionally the manufacturer should provide the applicant with the written assurance that the manufacturing process has not been modified since the granting of the certificate of suitability by the EDQM.

In case a new or updated certificate of suitability has been issued, the applicant should submit it through the relevant variation procedure.

This procedure is aimed at facilitating and simplifying exchanges between the partners to ensure that the quality of substances is guaranteed and that these substances comply with the European Pharmacopoeia, by issuing a so-called certificate of suitability (CEP or CEP for TSE).

CEPs are recognised by all signatory states of the European Pharmacopoeia Convention and by the European Union. There are also other countries which have also chosen to recognise them.

CEPs for biological substances of non-recombinant origin

Following the EDQM decision to exclude products classified as 'other biological substances' by the Coordination Group for Mutual Recognition and Decentralised Procedures - Human (CMDh) from the scope of the certification procedure, applicants are requested to submit full data in module 3 for new applications for marketing authorisation through the centralised procedure for medicinal products containing these biological substances. Existing certificates of suitability (CEPs) for these substances can be included in the dossiers but should not be used as replacement of the relevant data in the corresponding sections of module 3.

The reasoning behind this decision is that for biologicals, the characterisation and determination of the quality of these products requires not only a combination of physicochemical and biological testing, but also extensive knowledge of the production process and its control.

The EDQM will therefore not accept any new applications for CEPs for these biological substances.

List of standard terms and its use

The list of the standard terms was drawn up by the European Pharmacopoeia Commission for use in the MAA and the product information (summary of product characteristics [SmPC], labelling and package leaflet). It has the dual purpose of bringing information to the patient, user and prescriber, and distinguishing the various presentations of a medicinal product. It should convey essential information on the properties and use of the particular medicinal-product presentation.

The standard term concerns the pharmaceutical form, the route of administration or container. The pharmaceutical-form standard term consists of a combination of the form in which a medicinal product is presented (form of presentation) and the form in which it is administered, including the physical form (form of administration). In special cases (e.g. identical products that may be distinguished only by reference to the container), the information about the immediate container can be included in the pharmaceutical form, e.g. 'solution for injection in prefilled syringes'.

Moreover, due to the specificity of a medicinal product, the complete characterisation of a pharmaceutical form may be constructed by using a combination of existing standard terms, e.g. 'powder for solution for injection or infusion'.

The route of administration indicates the part of the body on which, through which, or into which the medicinal product is to be administered.

The container is the packaging immediately in contact with the medicinal product.

When the nature of the medicinal product is such that no existing standard term or combination of standard terms accurately describes the product presentation, a request for a new standard term will have to be made to the EDQM. The need for such a request should be identified by the applicant preferably during the European Medicines Agency presubmission meeting. The applicant should submit the request for a new standard term to the Agency, together with appropriate supportive documentation i.e. a detailed description of the pharmaceutical form and proposed new term, together with a justification for the new term including why any of the existing terms are not appropriate, and a draft SmPC. The request will be reviewed by the Working Group on Quality Review of Documents and the Quality Working Party. The Agency will subsequently forward the applicant’s request and the common Agency position to the EDQM for final decision.


53. When do I have to submit an environmental-risk assessment? Rev. October 2014

In accordance with Article 8(3) (ca) and (g) of Directive 2001/83/EC, as amended, the evaluation of the potential environmental risks posed by medicinal products should be submitted, their environmental impact should be assessed, and on case-by-case basis, specific arrangements to limit the impact should be considered. In any event this impact should not constitute a criterion for refusal of a marketing authorisation for medicinal products for human use.

The environmental risk assessment (ERA) concerns the risks to the environment arising from the use, storage, and disposal of the medicinal product. Risks arising from the synthesis or manufacture of the product are under the remits of the national competent authorities.

The ERA follows a step-wise, two-phase procedure. The first phase (phase I) estimates the exposure of the environment to the drug substance by calculating the predicted environmental concentration (PEC). The PEC calculation applies to the aquatic compartment (PECSURFACEWATER). If the PECSURFACEWATER value is equal or above 0.01 μg/L, then a phase II environmental-fate and effect analysis should be performed.

More details are provided in the guideline on the environmental risk assessment of medicinal products for human use and in the related 'Questions and Answers on Guideline on the environmental risk assessment of medicinal products for human use' document.

An ERA is required for all new MAAs for a medicinal product through a centralised, mutual recognition, decentralised and national procedure including applications submitted under Article 10 of the mentioned directive.

The ERA, including the relevant study reports, should be provided in module 1.6 of the MAA together with the dated signature of the author, information on the author’s educational, training and occupational experience (curriculum vitae) and a statement of his or her relationship with the applicant.

In the case of medicinal products containing natural substances e.g. vitamins, electrolytes, amino acids, peptides, proteins, carbohydrates, lipids and of vaccines and herbal medicinal products, a justification for not submitting ERA studies should be provided in module 1.6.

In case of an existing marketing authorisation, a re- evaluation of the ERA should be submitted with the application for type II variations or for extension applications.

An ERA is not required for renewals or Type IA/IB variations.

Studies in the context of an ERA are expected to be assessed during the initial marketing authorisation or relevant post-marketing procedures (e.g. extension of indication, extension applications). In the exceptional case that ERA study results are provided stand-alone, they should be submitted as a type IB C.1.z variation as described in the Practical questions and answers to support the implementation of the variations guidelines in the centralised procedure.


54. How are ATC codes and international non-proprietary names applied within the centralised procedure? Rev. November 2015

ATC codes

The Anatomical Therapeutic Chemical (ATC) classification is a system in which medicinal products are divided into different groups according to the organ or system on which they act and their chemical, pharmacological and therapeutic properties. The medicinal products are classified in groups at five different levels.

The applicant for a marketing authorisation should apply for an ATC code using the application form on international language for drug utilization research. This website also gives information on data to be submitted.

Within the Centralised Procedure, the ATC code is used in the application form for a Marketing Authorisation (MA) and in the Summary of Products Characteristics (SPC). The Applicant should bear in mind that, if an ATC code is not yet assigned to the Medicinal Product, no temporary code should be mentioned in the SPC and “Not yet assigned”, should appear in section 5.1 of the SPC. The proposed/temporary code should however be mentioned in the application form for a MAA. If an ATC code has been assigned, it should be given in section 5.1 of the SPC without any spaces and without brackets (e.g. N02BE01).

When the applicant receives the final ATC code from the World Health Organization (WHO), the Agency should be informed as soon as possible in writing, if this happens before CHMP opinion, with the appropriate proof of the change in status from WHO. The SmPC should also be amended accordingly. If the ATC code is obtained after opinion, the Agency should be informed and the SmPC should be amended accordingly either as a type-IA variation or at the occasion of another variation after the Commission decision has been obtained. The same procedure applies in cases where a revision of a final ATC code by the WHO for medicinal products already authorised.

International non-proprietary names

An international non-proprietary name (INN) identifies a pharmaceutical substance or active pharmaceutical ingredient by a unique name that is globally recognised and is public property. The aim of the INN system has been to provide health professionals with a unique and universally available designated name to identify each pharmaceutical substance. To make INNs universally available, they are formally placed by WHO in the public domain, hence their designation as 'non-proprietary'.

The names, which are given the status of an INN, are selected by the WHO on the advice of experts from the WHO Expert Advisory Panel on the International Pharmacopoeia and Pharmaceutical Preparations. The process of INN selection follows three main steps:

  1. A request or application is made by the manufacturer or inventor, using an INN request form from the WHO.
  2. After a review of the request, a proposed INN is selected and published for comments in WHO drug information.
  3. After a time period for objection has lapsed, the name will obtain the status of a recommended INN and is published as such by the WHO in WHO drug information if no objection has been raised.

If applicants for MA wish to apply for an INN, it is strongly recommended that they liaise with WHO well in advance of MA submission, in order to obtain a recommended INN for their pharmaceutical substance as soon as possible and preferably no later than the CHMP opinion is obtained. Within the centralised procedure, the INN is used throughout the MA dossier. 

If a recommended INN is not available at submission, the proposed INN can be used in the application form and in the product information (PI). When the applicant receives the recommended INN from the WHO, if this happens before CHMP opinion, the Agency should be informed as soon as possible in writing with the appropriate proof of the change in status from WHO and the PI should be amended accordingly. If the INN is obtained after opinion, the Agency should be informed and the PI should be amended accordingly either as a type-IA variation or at the occasion of another variation after the Commission decision has been obtained.

For certain biologicals, because of their complexity, general rules for INN are not easily formulated. Some of these substances may have descriptive names assigned by other institutions. These names may not be suitable as INNs. Some nomenclature schemes for groups of biological compounds are provided in INNs for biological and biotechnological substances.

For vaccines, the INN is not applicable and in these cases either the pharmacopoeial or common name of the antigens should be used.

In the absence of an INN, the common name or scientific name of the pharmaceutical substance should be used.


55. Can I apply for design space or process analytical technology in my application? New March 2007

The International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q8 (pharmaceutical development) introduces the notion of design space, defined as the multidimensional combination and interaction of input variables (e.g. material attributes) and process parameters that have been demonstrated to provide assurance of quality. The design space is proposed by the applicant as part of the MAA and thus is subject to assessment.

Additionally, the establishment of a robust design space is in line with new approaches on quality that focus on building quality into the medicinal product by design (the so-called quality-by-design concept).

Process analytical technology is defined as a system for analysing and controlling manufacturing through timely measurements (i.e. during processing) of critical quality and performance attributes of raw and in-process materials and processes with the goal of ensuring final product quality.

PAT is a tool that allows enhanced control of the manufacturing process, can improve process understanding and so facilitates building quality into products and the development of a design space. ICH Q9 (quality risk management) provides an approach and a selection of tools that can be used to manage risks associated with these processes.

The main PAT tools are:

  • multivariate data acquisition and analysis;
  • modern process analysers or process analytical chemistry tools;

The introduction of the PAT system can bring a number of advantages:

  • possibility of introducing 'real-time release';
  • reduction of cycle times;
  • improved product quality;
  • possibility of more efficient and effective control of some changes.

The introduction of PAT systems can be applied to new or existing authorised medicinal products.

When should I inform the Agency of the introduction of PAT or design-space approaches in my application?

Where design-space concepts or PAT approaches are used, MA applicants should indicate this in their letter of intent. It is of interest for the Agency and CHMP to be aware of their use so that this can be taken into account in the appointment of (co-)rapporteurship, as particular expertise from (co-)rapporteurs may be needed.

In addition, when requesting a presubmission meeting, the applicant should identify this in the relevant question in the presubmission request form.

The role of the Agency's PAT team

The Agency's PAT team is a forum for dialogue and understanding between QWP, BWP and the Ad-Hoc Group of GMP Inspection Services to prepare a harmonised approach in Europe on assessment of applications and inspections of products, systems and facilities for PAT, including quality-by-design principles and manufacturing science in the context of PAT. 

The PAT team may be consulted through the QWP or BWP during the assessment of a centralised MAA. Applicants using a PAT approach are encouraged to look at the PAT-related guidance and questions and answers provided. 

If there are still questions or issues that are not addressed through those documents, applicants could take the opportunity to contact the Agency's PAT team at early stage of pharmaceutical development. It should be noted that the PAT team only provides informal and non-binding advice which does not substitute for scientific advice or protocol assistance.

Presentation of PAT-related data in the application

When an application for, or variation to, a marketing authorisation is submitted, supporting documentation should be provided in accordance with CTD requirements (module 3). In addition, the expert report provided in module 2 (quality overall summary) should include a critique highlighting the positive and negative aspects of the design-space or PAT approach. 

For more information, see reflection paper: chemical, pharmaceutical and biological information to be included in dossiers when PAT is employed.

Applicants should note that submission of applications that include design space or PAT aspects could result in a specific product-related inspection at the manufacturing site.


56. Could my application qualify for a conditional marketing authorisation? New July 2007

Criteria and general provisions

For certain categories of medicinal products, in order to meet unmet medical needs of patients and in the interest of public health, it may be necessary to grant marketing authorisations on the basis of less complete data than is normally required. In such cases, it is possible for the CHMP to recommend the granting of a marketing authorisation subject to certain specific obligations to be reviewed annually ('conditional marketing authorisation').

This may apply to medicinal products for human use that fall under Article 3(1) and (2) of Regulation (EC) No 726/2004 and belong to one of the following categories:

  • medicinal products that aim at the treatment, the prevention or the medical diagnosis of seriously debilitating diseases or life-threatening diseases;
  • medicinal products to be used in emergency situations, in response to public threats duly recognised either by the WHO or by the Community in the framework of Decision (EC) No 2119/98;
  • medicinal products designated as orphan medicinal products in accordance with Article 3 of Regulation (EC) No 141/2000.

A conditional marketing authorisation may be granted where the CHMP finds that, although comprehensive clinical data referring to the safety and efficacy of the medicinal product have not been supplied, all the following requirements are met:

  • the risk-benefit balance of the medicinal product, as defined in Article 1(28a) of Directive 2001/83/EC, is positive;
  • it is likely that the applicant will be in a position to provide the comprehensive clinical data;
  • unmet medical needs will be fulfilled;
  • the benefit to public health of the immediate availability on the market of the medicinal product concerned outweighs the risk inherent in the fact that additional data are still required.

The legal basis for a conditional marketing authorisation is Article 14 (7) of Regulation (EC) No 726/2004. The provisions for the granting of such an authorisation are laid down in Regulation (EC) No 507/2006, adopted on 29 March 2006.

The granting of a conditional marketing authorisation should be restricted to situations where only the clinical part of the application dossier is not yet fully complete. Incomplete non-clinical or quality data should only be accepted if duly justified and only in the case of a product intended to be used in emergency situations, in response to public-health threats.

Conditional marketing authorisations are valid for one year, on a renewable basis. The holder will be required to complete ongoing studies or to conduct new studies with a view to confirming that the benefit-risk balance is positive. In addition, specific obligations may be imposed in relation to the collection of pharmacovigilance data.

The granting of a conditional marketing authorisation will allow medicines to reach patients with unmet medical needs earlier than might otherwise be the case, and will ensure that additional data on a product are generated, submitted, assessed and acted upon.

Prior to submission

Applicants for a potential conditional marketing authorisation may request CHMP scientific advice or protocol assistance, as applicable, on whether a specific medicinal product being developed for a specific therapeutic indication falls within one of the categories set out in Article 2 and fulfils the requirement laid down in Article 4(1)(c) ('unmet medical needs will be fulfilled') of Regulation (EC) No 507/2006. 

In addition, the intention to request a conditional marketing authorisation and any practical or procedural issues with regards to a potential request for conditional marketing authorisation should be addressed at the presubmission meeting.

Timing of the submission and documentation to be supplied

At least seven months before submission, applicants should notify the Agency of their intention to submit an application and include a statement on the intention to request a conditional marketing authorisation (in accordance with Article 14(7) of the Regulation).

The applicant may present a request for a conditional marketing authorisation at the time of the application for marketing authorisation.

If the applicant considers that the grounds for a conditional marketing authorisation apply, the applicant should tick the box 1.5.1 of the application form and include its justification in module 1.5.5. Such a justification should show that the medicinal product falls within the scope of the conditional marketing authorisation Regulation (Article 2) and that the requirements for conditional marketing authorisation are fulfilled (Article 4), together with the applicant’s proposal for completion of ongoing or new studies, or the collection of pharmacovigilance data. The request may cross-refer to specific parts of the application.

Upon receipt of a valid application containing a request for conditional marketing authorisation, the Agency will inform the European Commission.

For further guidance on the criteria for conditional marketing authorisations, justifications to be provided and the procedure to be followed, see the guideline on the scientific application and the practical arrangements necessary to implement Commission Regulation (EC) No 507/2006 on the conditional marketing authorisation for medicinal products for human use falling within the scope of Regulation (EC) No 726/2004.

CHMP assessment of a request for conditional marketing authorisation

The rapporteur, co-rapporteur and other CHMP members will assess the justification and data submitted for a conditional marketing authorisation as part of the overall assessment of the benefit-risk balance of the application. The assessment of the justification will be reflected in the relevant assessment reports and in the final CHMP assessment report.

A conditional marketing authorisation may be requested by the applicant or proposed by the CHMP. Therefore, during the scientific assessment, after having consulted with the applicant, the CHMP may also propose a conditional marketing authorisation. Normally, the proposal and explanatory reasons will be given to the applicant in the day-120 list of questions, or exceptionally later, in the day-150 joint assessment report and day-180 list of outstanding issues. The reasons for proposing a conditional marketing authorisation will also be detailed in the relevant assessment reports and in the CHMP assessment report.

Upon granting of a conditional marketing authorisation, the specific obligations and the timeframe for their completion will be clearly specified in the conditional marketing authorisation (Annex II.C to the Commission decision), and will be made publicly available by the Agency as part of the European public assessment report.

Information included in the summary of product characteristics and package leaflet

In order to provide clear information to patients and healthcare professionals on the conditional nature of the authorisations, the summary of product characteristics and package leaflet will mention that a conditional marketing authorisation has been granted subject to certain specific obligations to be reviewed annually.

Differences between conditional marketing authorisations and marketing authorisations under exceptional circumstances

Conditional marketing authorisations are distinct from marketing authorisations granted in exceptional circumstances in accordance with Article 14(8) of Regulation (EC) No 726/2004. In the case of the conditional marketing authorisation, an authorisation is granted before all data are available. The authorisation is not intended, however, to remain conditional indefinitely. Rather, once the missing data are provided, it should be possible to replace it with a marketing authorisation which is not conditional, that is to say, which is not subject to specific obligations. In contrast, it will normally never be possible to assemble a full dossier in respect of a marketing authorisation granted in exceptional circumstances.

Conditional marketing authorisationMarketing authorisation under exceptional circumstances
Demonstrate positive benefit-risk balance, based on scientific data, pending confirmationComprehensive data cannot be provided (specific reasons foreseen in the legislation)
Authorisation valid for one year, on a renewable basisReviewed annually to re-assess the risk-benefit balance, in an annual re-assessment procedure
Once the pending studies are provided, it can become a 'normal' marketing authorisationReviewed annually to re-assess the risk-benefit balance, in an annual re-assessment procedure


How useful is this page?

Average rating:

 Based on 13 ratings

Add your rating:

See all ratings
5 ratings
1 ratings
0 ratings
4 ratings
3 ratings