Presubmission guidance: questions 41 to 50

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This page lists questions 41 to 50 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.

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41. What is the period of protection for my medicinal product? - New Jul 2006

Data exclusivity and market exclusivity period for reference medicinal products

A reference medicinal product is a medicinal product, which has been granted a marketing authorisation by a Member State or by the Commission on the basis of a complete dossier, i.e. with the submission of quality, pre-clinical 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.

See also question "What is the legal basis for my application?"

  • 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 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 form, 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 these 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 form, administration routes, presentations as well as any variation and 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.

- The "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 products’ 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 8 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 of 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 pre-clinical 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 pre-clinical 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 reads: "Where a change of classification of a medicinal product has been authorised on the basis of significant pre-clinical 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 1-year period of protection covers significant pre-clinical 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 pre-clinical 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 pre-clinical 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 pre-clinical tests or clinical trials.

(See also 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 1 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 draft Guideline on aspects of the application of Article 8 of Regulation (EC) No 141/2000

References:

42. How shall I submit my EU Risk Management Plan as part of my application? Rev. May 2013

Description of the risk management system

Article 8(3) ((iaa)) of Directive 2001/83/EC requires that a marketing authorisation application (MAA) shall include the risk management plan describing the risk management system which the applicant will introduce for the medicinal product concerned, together with a summary thereof.

A Risk Management Plan (RMP) is a detailed description of the risk management system that in itself is a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to medicinal products including the assessment of the effectiveness of those activities and interventions.

The aim of a risk management system is to ensure that the benefits of a particular medicine (or a series of medicines) exceed the risks by the greatest achievable margin for the individual patient and for the target population as a whole.

When should I submit my RMP?

An initial RMP or an update may need to be submitted at any time during a product’s lifecycle, i.e. during both pre- and post-authorisation phases. Detailed information when an initial or updated RMP should be submitted can be found in Guideline on good pharmacovigilance practices (GVP) Module V – Risk management systems.

For initial marketing authorisation applications the RMP should be submitted together with the application dossier in eCTD module 1.8.2. A RMP or an update of the RMP is also expected together with an application involving a significant change to an existing marketing authorisation (extension of indication, line extension, new manufacturing process of a biotechnologically-derived product); and at the request of the Agency or national competent authority.

When should updates of the RMP be submitted?

The MAH should submit updates of the RMP if information becomes available that has an impact on the benefit-risk profile of the medicinal product(s) included in the RMP. E.g. when new information is received that may impact on the current Safety Specification, Pharmacovigilance Plan, assumptions regarding efficacy or risk minimisation measures; or within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached. An update of the RMP should also be submitted at the request of a Competent Authority.

Updates to the RMP should also be submitted with an application involving a significant change to an existing marketing authorisation (extension of indication, line extension, new manufacturing process of a biotechnologically-derived product) if there is already an existing RMP in place.

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 EU-RMP for a medicinal product seeking a new authorisation through the centralised procedure should take place at the pre-submission meeting.

To whom shall I submit a stand-alone RMP?

The EMA strongly recommends using the eSubmission Gateway or the eSubmission Web Client as the preferred submission method for all eCTD submissions. More information on how to register and connect to the Gateway / Web Client can be found in the eSubmission website and detailed information on the required naming conventions and file formats can be found in the eSubmission Gateway Q&A document and the Web Client Q&A. Applicants must not send duplicate submissions electronically or via CD-ROM or DVD as this might lead to delays in the handling of applications.

Applications that are sent using the eSubmission Gateway and eSubmission Web Client will receive an automated ‘acknowledgement’, confirming whether the submission has passed the relevant technical validation criteria and whether it has been uploaded to the agency’s review tool. There is no need to send any separate paper cover letters for these submissions, as the cover letter will be in the relevant part of eCTD module 1 in PDF format.

MAHs not yet using the eSubmission Gateway or the Web Client solution should send their submission as CD-ROM or DVD to the attention of the Product and Application Business Support (PA-BUS) at the following address:

Product and Application Business Support (PA-BUS)
European Medicines Agency
Loading Dock
Ontario Way
Canary Wharf
UK - London, E14 4HB

Only one CD-ROM or DVD (in eCTD format) of the RMP should be submitted to the Agency, together with one original, signed cover letter when using this format of submission. The Product Team Leader should be indicated in copy (“cc”) on the cover letter (no additional copy needed).

One electronic copy of the RMP submission and supportive documentation should also be sent to the (Co-) Rapporteur and other members, after the eSubmission Gateway / Web Client confirmation of a technically valid submission at the time of submission, to maintain the life cycle of the eCTD dossier.

It is essential that identical eCTD sequences are circulated to Committee Members. Any minor changes that affect the “md5 checksum” will lead to inconsistency and possibly result in future technical invalidity. Where applications are amended during the agency’s review, such as e.g. responses to a request for supplementary information or a withdrawal, new or consolidated eCTD sequence should be provided in order to maintain the eCTD life-cycle. The same applies in case the outcome of the variation application review is unfavourable for one or more changes applied for (mixed outcome). Please refer to the TIGes Harmonised Guidance and to the Question and Answer document under the New Variation Regulation and eCTD for specific advice.

For a full overview of dossier requirements for National Competent Authorities of (Co)Rapporteur and Committee members, including delivery addresses, please refer to the following document: Dossier requirements for Centrally Authorised Products (CAPs).

Please note that the EMA only accepts submissions made in a mandatory eCTD format.

References

How shall I present my RMP?

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

  • All new procedures submitted after the 10th of January and subsequently starting containing a (updated) RMP as well as stand-alone RMP submissions should follow the guidance and be submitted in the new format.
  • All initial MAAs and line extensions, having been submitted before the 10th of January, but having their D121 or D181 responses submitted after the 10th of April will have to comply with the new RMP format, i.e. the responses will always have to contain an updated RMP according to the new guidance
  • All other post-authorisation procedures containing a RMP or stand-alone RMP submissions, having been submitted before the 10th of January will not have to provide within responses an updated RMP in line with the guidance.

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.

For updates of existing RMPs, clean and track change versions should be submitted along with a cover letter detailing the changes since the last submitted version.

For versioning of the RMP the numbering should be consecutive and without added text. The numbering is independent of whether the RMP was endorsed by the CHMP or not.
The new version of the RMP should be dated.

How do I submit the EU RMP in eCTD ?

The revised RMP should be provided in CTD section 1.8.2

Until further notice companies have to send in all parts and modules of the RMP in one single PDF-file so that a complete RMP is provided to the Agency. A cover letter stating which parts and/or modules of the RMP have actually been updated should be provided. Part I of the RMP also presents this information and should always be updated.

Should I provide documents with tracked changes highlighted to facilitate review?

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 MS Word or Rich Text Format (rtf) in the separate folder ‘XXXX-working documents’ on the same CD / DVD. Further details can be found in section 2.9.9 of the TIGes Harmonised Guidance for eCTD Submissions in the EU.

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.

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.

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

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

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

The submission of a risk management plan 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.

What are the requirements for a RMP for a new application of an established generic product?

Marketing authorisation applications for a generic medicinal product under Article 10(1) of Directive 2011/83/EC submitted after 2nd July 2012 will have to include a 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 page 54-55).

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?

The company of the generic medicinal product should use the (E)PAR and the SmPC of the reference medicinal product to obtain the safety concerns to be included in module SVIII of the RMP. Companies may also discuss with the relevant competent authority what safety concerns should be included.

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 characterize 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 PhV Plan.

Studies in the PIP should not be routinely included in the PhV 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 PhV 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.

How is the assessment of an educational program as additional risk minimisation handled?

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.

Can the internet be used as additional risk minimisation measure (e.g. website with educational material/video)?

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.

Should I submit a summary of the RMP and will it be published?

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

Guidance on the format and content of the RMP for MAA/MAH, including the RMP summary, is published on the Agency’s website. Part VI contains summarised information on the RMP, which will be prepared by the MAH and assessed as part of the normal evaluation process.

A RMP summary is required for all medicines authorised. The current approach is that subsequent updates in the new format will be used to ensure all medicines have a RMP summary.

The final format of the RMP summary and processes for its production and publication are still subject to discussion. Further details will be published on the Agency website and those of national competent authorities (as appropriate) as soon as these are available.  However, it is highly likely that the published summary will be based on the elements provided in Part VI of the RMP.

How will the PRAC be involved in the review of my RMP?

The oversight of RMPs for products authorised centrally lies with the PRAC. The PRAC is involved in procedural and scientific matters regarding RMPs since September 2012.

  • Initial MAA submitted as of 2 July with a start in August 2012 and thereafter
  • Ongoing initial MAA for which D121 re-starts as of October 2012
  • For Extension application / Extension of indication when including a new or updated RMP and if submitted as of 2 July 2012
  • New or updated RMP submitted in parallel of a PSUR as of 2 July 2012
  • For stand-alone new or updated RMP submitted as of 4 August 2012

PRAC provides ‘Advice’ to CHMP on RMPs for CAPs.

The PRAC Advice is included in the minutes of the PRAC meeting which will be published on the EMA website.

References

For GVPs that have not been published yet, Volume 9A remains the reference document if needed.

Should I provide documents with tracked changes highlighted to facilitate review? New May 13

When submitting an existing RMP for the first time in the new format, track change should not be used. However, a content change overview should be provided to identify which parts/sections of the RMP have been updated as a result of new data – ie those parts which would have subject to track changes if the RMP had been submitted in the old format.

Can I submit a version of the RMP after the Opinion to reflect the last minute changes made during the CHMP? New May 13

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.

e.g.:

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.

43. Pharmacovigilance system - Rev. March 2013

Requirements regarding the summary of the pharmacovigilance system

Companies are requested to provide a summary of their pharmacovigilance system, which the applicant/marketing authorisation holder (MAH) will introduce, in accordance with Article 8(3)(ia) of Directive 2001/83/EC.

The requirement for the summary of the pharmacovigilance replaces the previous requirement for the detailed description of pharmacovigilance system in the dossier.

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

  • proof that the applicant has at his disposal a qualified person responsible for pharmacovigilance,
  • the Member States in which the qualified person resides and carries out his/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) “the applicant has the necessary means to fulfil the tasks and responsibilities listed in Title IX of Directive 2001/83/EC”, signed by the applicant and qualified person for pharmacovigilance (QPPV).

Applicants are required to include a summary of the applicant pharmacovigilance system at the time of submission of an initial marketing authorisation application (MAA).

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

Requirements regarding the pharmacovigilance system and pharmacovigilance system master file

The MAH has to operate a pharmacovigilance system for the fulfilment of his 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 7 days to the Competent Authorities if requested. The PSMF must be located either at the site in the Union where the main pharmacovigilance activities of the marketing authorisation holder are performed or at the site in the Union where the QPPV operates. The QPPV has to both reside and operate in the Union.

Applicants are required, at the time of initial marketing authorisation application, 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 a marketing authorisation application the applicant may be requested to provide a copy of the pharmacovigilance system master file for review.

The pharmacovigilance system master file 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. He will nevertheless retain full responsibility for the completeness and accuracy of the pharmacovigilance system master file.

The MAH will have to draw up a list of its existing subcontracts between himself and the third parties, specifying the product(s) and territory(ies) 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 pharmacovigilance system master file location, maintenance of the pharmacovigilance system master file and its provision to competent authorities upon request. Detailed written agreements describing the roles and responsibilities for pharmacovigilance system master file 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 Good Vigilance Modules.

Pharmacovigilance system master file number

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

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 Detailed guidance on electronic submission of information on medicines.

References

44. What is the CHMP Peer Review? - New Oct 2006

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/regulatory conclusions reached. It applies during the initial phase of the assessment of a new Marketing Authorisation Application (MAA).

Peer review is part of a quality assurance system established at CHMP level. That is the review of the (Co) Rapporteurs' assessment reports for the purpose of improving the quality of the day 120 List of Questions by those 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 EMA Road Map to 2015.

On appointment of (Co) Rapporteurs during a CHMP meeting, the Committee also appoints Peer Reviewers. The Peer Reviewer’s 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, and/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 (Co) Rapporteurs, Peer Reviewers and EMA staff to discuss and critically analyse the different objections and concerns raised in the (Co) Rapporteur’s "Overview and draft List of Questions".

Peer Reviewer’s 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 a MAA.

References:

45. 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 can be found on the European Union website:

http://eur-lex.europa.eu/en/treaties/index.htm 

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 the Annex I to Chapter 1 of the Notice to Applicants (the Rules governing Medicinal Products in the European Community, Notice to Applicants, Volume 2A, Chapter 1)

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

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/index.htm

  • Volume 1 – Pharmaceutical legislation, contains most of the relevant Directives, Regulations, Decisions and Communications
  • Volume 2 – Notice to Applicants (mentioned above)
    • Volume 2A - Procedures for marketing authorisation, is organised as follows:
      • 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, is related to procedural and regulatory requirements e.g. renewal procedures, variation procedures, summary of product characteristics (SPC), package information and classification for the supply, readability of the label and package leaflet requirements.
  • Volume 3 – Scientific guideline
  • Volume 4 – Good Manufacturing Practices
  • Volume 9 – Pharmacovigilance
    With the application of the new pharmacovigilance legislation as from July 2012 Volume 9A is replaced by the good pharmacovigilance practice guidelines (GVP) released by the European Medicines Agency. However, until the availability of the respective GVP modules Volume 9A remains the reference.
    • The 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 which provides details on the operational aspects for the new legislation: http://eur-lex.europa.eu/LexUriServ/LexUriServ.do?uri=OJ:L:2012:159:0005:0025:EN:PDFVolumes 5, 6, 7 and 8 apply only to veterinary medicinal products
  • 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.

The scientific guidelines related to quality, safety and efficacy can be found at the EMA website. It also includes concept papers, draft guidelines and overview of comments received during the consultation on draft versions:

The EMA also publishes on its website 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:

References:

46. Which European Directorate for the Quality of Medicines and HealthCare (EDQM) activities impact on the centralised procedure? - Rev. Jul 2010

Introduction

The European Directorate for the Quality of Medicines & 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.
  • Co-ordinating activities performed by Official Medicines Control Laboratories network including annual sampling and testing programme for Centrally Authorised Products (CAPs) within the setting of a network.
  • Co-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.

The EDQM representatives participate as observers to the Agency’s Quality Working Party (QWP) and Biologics Working Party (BWP) meetings, the GMP inspection services group meetings as well as HMPC meetings at the European Medicines 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 refer to the mandatory character of European Pharmacopoeia monographs in the preparation of dossiers for Marketing Authorisation Applications (MAA).

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, as well as dosage forms and containers. The texts of the European Pharmacopoeia also apply to biologicals, blood and plasma derivatives, vaccines and radio-pharmaceutical preparations.

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

Additionally, chemical and biological reference material of the European Pharmacopoeia (Chemical Reference Substances 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 shall be replaced by the appropriate detailed reference to the monograph(s) and general chapter(s).

What is the scope of the Certification Procedure of the EDQM?

The Certification Procedure is intended for substances for which a monograph (general monograph and/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; or
  • The evaluation of the reduction of Transmissible Spongiform Encephalopathy (TSE) risk, according to the general monograph; or,
  • Both of the above; or,
  • The evaluation of the suitability of the monograph for the control of herbal drugs and herbal drugs preparations.

A CEP can be used by the manufacturers of pharmaceutical products in their marketing authorisation applications 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, the applicants are exempted of providing the concerned data in the relevant parts of Module 3 of the MAA, as 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/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.

Note on CEPs for biological substances of non-recombinant origin

Following EDQM decision to exclude from the scope of the certification procedure the products classified as “other biological substances” by the CMD (h). Applicants are requested to submit full data on the 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 physico-chemical and biological testing, but also extensive knowledge over the production process and its control.

The EDQM will therefore not accept any new application for a CEP 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 marketing authorisation application and the product information (SPC, labelling, package leaflet). It has the double purpose of bringing information to the patient/user/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 either the pharmaceutical form, 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 which 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 pre-filled 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 EMA pre-submission meeting. The applicant should submit to the EMA the request for a new standard term, 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 SPC. The request will be reviewed by the Quality Review of Documents and the Quality Working Party groups. The EMA will subsequently forward the applicant’s request and the common EMA position to the EDQM for final decision.

References:

47. When do I have to submit an Environmental Risk Assessment (ERA)? - New Mar 2007

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.

The Environmental Risk Assessment (ERA) concerns the risks to the environment arising from the use, storage, and disposal of the medicinal product not to risks arising from the synthesis or manufacture of the product. 

The assessment of the potential risks is 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 is restricted 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 environmental risk assessment of medicinal products for human use.

An ERA is required for all new marketing authorisation applications (MAA) for a medicinal product through a centralised, mutual recognition, decentralised and national procedure.

The ERA or the justification for not providing it should be provided in Module 1.6, together with a dated signature of the author, information on the author’s educational, training and occupational experience (CV) and a statement of his/her relationship with the applicant.

For paper submissions, if the ERA consists of extensive documentation it should be provided in a separate volume as part of Module 1.

In case of an existing marketing authorisation, the evaluation of the environmental impact should be submitted with the application for type II variations or for extension applications according to Annex II of Commission Regulation (EC) No 1085/2003, if there is an increase in the environmental exposure.

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

References:

48. How are the ATC codes/INN applied within the Centralised Procedure? - New Mar 2007

1. 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 the WHO website. For information on data to be submitted together with the application form please refer to the WHO website (www.whocc.no).

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, stating its status in brackets. 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 WHO, if this happens before CHMP opinion, the EMA should be informed as soon as possible in writing with the appropriate proof of the change in status from WHO and the SPC should be amended accordingly. If the ATC code is obtained after opinion, the EMA should be informed and the SPC 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 case of a revision of a final ATC code by the WHO for medicinal products already authorised.

2. INN

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:

  • A request/application is made by the manufacturer or inventor, using an 'INN request form' from WHO website (www.who.int)
  • After a review of the request a proposed INN is selected and published for comments in WHO Drug Information
  • 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 if no objection has been raised

If applicants for Marketing Authorisation (MA) wish to apply for an INN, it is strongly recommended to 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 EMA 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 EMA 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 the WHO guideline.

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

References:

49. Can I apply for Design Space or Process Analytical Technology (PAT) in my application? - New Mar 2007

The 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 which focus on building qualityinto the medicinal productby design (the so-called QbD concept)

PAT 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 which 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:

  • Possibilities to introduce "real time release";
  • Reduction of cycle times;
  • Improved product quality;
  • Possibilities for more efficient and effective control of some changes;

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

When to inform the EMA of the introduction of PAT or Design Space approaches in my application

- Where Design Space concepts or PAT approaches are used, Marketing Authorisation 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 it 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 pre-submission meeting, the applicant should identify it in the relevant question of the pre-submission request form.

The role of the EMA PAT team

The EMA Process Analytical Technology Team is a forum for dialogue and understanding between Quality and Biologics Working Parties and Ad-Hoc Group of GMP Inspection Services to prepare a harmonised approach in Europe on assessment of applications and inspections of products / systems / facilities for Process Analytical Technology, including quality by design principles and manufacturing science in the context of PAT. 

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

If there are still questions or issues which are not addressed through those documents, applicants could take the opportunity to contact the EMA 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/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 on chemical, pharmaceutical and biological information to be included in dossiers when Process Analytical Technology (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.

References:

50. Could my application qualify for a conditional marketing authorisation? - New Jul 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 which 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 and/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 will be 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 risk-benefit 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 pre-submission meeting.

Timing of the submission and documentation to be supplied

At least seven months before submission, applicants should notify the EMA 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 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 EMA will inform the Commission.

For further guidance on the criteria for conditional marketing authorisations, justifications to be provided and the procedure to be followed, reference is made to the draft guidance document published on the EMA website (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 the other CHMP members will assess the justification/data submitted for a Conditional Marketing Authorisation as part of the overall assessment of the benefit/risk 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 EPAR.

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 Authorisation and Marketing Authorisation under 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 reassess 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 reassess the risk-benefit balance, in an annual re-assessment procedure

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.

References:

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