VII.C.3. List of European Union reference dates and frequency of submission of PSURs20

Location:
VII.C.

VII.C.3.1. Objectives of the EU reference dates list

The Agency shall make public a list of Union reference dates (hereinafter referred to as list of EU reference dates) and frequency of submission of PSURs by means of the European medicines webportal [DIR Art 107c(7), REG Art 26(1)(g)].

The objectives of the list of EU reference dates and frequency of submission of PSURs are:

  • Harmonisation of data lock point and frequency of submission of PSURs for the same active substance and combination of active substances: For medicinal products containing the same active substance or combination of active substances subject to different marketing authorisations, an EU reference date should be set up and the frequency and date of submission of PSURs harmonised in order to allow the preparation of a single assessment established in DIR Art 107e(1). Such information should be included in the list published by the Agency.
  • Optimisation of the management of PSURs and PSURs assessments within the EU: The list overrules the submission schedule described in DIR Art 107c(2)(b). For active substances or combinations of active substances included in the list, marketing authorisation holders shall vary, if applicable, the condition laid down in their marketing authorisations in order to allow the submission of PSURs in accordance to the frequency and submission date as indicated in the list [DIR 107c(4) to (7)]. The periodicity is defined on the basis of a risk-based approach in order to prioritise the periodic re-evaluation of the risk-benefit balance of active substances in a way that best protects public health [Directive 2010/84/EU Preamble Recital 23].
  • Single EU assessment and reassessment of the risk-benefit balance of an active substance based on all available safety data: The list enables the harmonisation of PSUR submissions for medicinal products containing the same active substance or the same combination of active substances. A single EU PSUR assessment provides a mechanism for evaluating the totality of available data on the benefits and risks of an active substance or combination of active substances. The effective application of work sharing principles is important in avoiding duplication of efforts and in prioritising the use of limited resources in the best interests of European citizens.

VII.C.3.2. Description of the EU reference dates list

The Union reference date of medicinal products containing the same active substance or the same combination of active substances shall be [DIR Art 107c(5)]:

  • the date of the first marketing authorisation in the EU of a medicinal product containing that active substance or that combination of active substances; or
  • if the date of first marketing authorisation cannot be ascertained, the earliest of the known dates of the marketing authorisations for a medicinal product containing that active substance or that combination of active substances.

The list of EU reference dates and frequency of submission of PSURs consists of a comprehensive list of substances and combinations of active substances in alphabetical order, for which PSURs, where required, shall be submitted in accordance with the EU reference date and the frequency as determined by the Committee for Medicinal Products for Human Use (CHMP) and the Coordination Group for Mutual Recognition and Decentralised Procedures – Human (CMDh) following consultation with the Pharmacovigilance Risk Assessment Committee (PRAC) [DIR Art 107c(4) and (6)].

The list should be updated in line with the “list of all medicinal products for human use authorised in the Union” as referred to in REG Art 57(1)(b). The EU reference dates list should contain the following information:

  • the EU reference dates;
  • the frequencies of submission of PSURs;
  • the data lock points of the next submissions of PSURs;
  • the date of publication (on the European Medicines web-portal) of the frequency for PSURs submission and data lock point for each active substance and combination of active substances. Any change to the dates of submission and frequency on PSURs specified in the marketing authorisation shall take effect 6 months after the date of such publication [DIR Art 107c(7)].

Where specificity is deemed necessary, the list should include the scope of the PSUR and related EU single assessment procedure (see VII.C.3.3.) such as:

  • whether or not it should cover all the indications of the substance or combination of active substances;
  • whether or not it should cover all the formulations/routes of administration of the products containing a substance or combination of active substances;
  • whether generic, well-established use, traditional herbal and homeopathic medicinal products shall submit a PSUR due to a request from a competent authority or due to concerns relating to pharmacovigilance data or due to the lack of PSURs relating to an active substance after the marketing authorisation has been granted [DIR Art 107c(2) second subparagraph] (see VII.C.3.3.2.).

VII.C.3.3. Application of the list of EU reference dates to submission of PSURs

VII.C.3.3.1. Submission of PSURs for medicinal products: general requirement

Figure VII.3. presents the various potential scenarios for the submission of a PSUR as a general requirement.

The data lock points included in the list of EU references dates enable the synchronisation of PSURs submission for products subject to different marketing authorisations and permit the EU single assessment. These data lock points are fixed on a certain date of the month, and should be used to determine the submission date (which has legal status) of the PSUR. Marketing authorisation holders can request to amend those dates in accordance with section VII.C.3.5.2.

Unless otherwise specified in the list of EU reference dates and frequency of submission, or agreed with competent authorities in Member States or the Agency, as appropriate, a single PSUR shall be prepared for all medicinal products containing the same active substance and authorised for one marketing authorisation holder. The PSUR shall cover all indications, routes of administration, dosage forms and dosing regimens, irrespective of whether authorised under different names and through separate procedures. Where relevant, data relating to a particular indication, dosage form, route of administration or dosing regimen shall be presented in a separate section of the PSUR and any safety concerns shall be addressed accordingly [IR Art 34(6)].

For medicinal products containing an active substance or a combination of active substances not included in the EU reference dates list, PSURs shall be submitted according to the PSUR frequency defined in the marketing authorisation or if not specified, in accordance with the submission schedule specified in DIR Art 107c(2) and REG Art 28(2).

VII.C.3.3.2. Submission of PSURs for generic, well-established use, traditional herbal and homeopathic medicinal products

By way of derogation, generics (authorised under DIR Art 10(1)), well-established use (authorised under DIR Art 10a), homeopathic (authorised under DIR Art 14) and traditional herbal (authorised under DIR Art 16a) medicinal products are exempted from submitting PSURs except in the following circumstances [DIR Art 107b(3)]:

  • the marketing authorisation provides for the submission of PSURs as a condition;
  • PSURs is (are) requested by a competent authority in a Member State on the basis of concerns relating to pharmacovigilance data or due to the lack of PSURs relating to an active substance after the marketing authorisation has been granted (e.g. when the “reference” medicinal product is no longer marketed). The assessment reports of the requested PSURs shall be communicated to the PRAC, which shall consider whether there is a need for a single assessment report for all marketing authorisations for medicinal products containing the same active substance and inform the CMDh or CHMP accordingly, in order to apply the procedures laid down in DIR Art 107c(4) and 107e.

In order to facilitate and optimise the PSUR EU single assessment process, to avoid duplications of requests for PSURs and to provide transparency and predictability for the marketing authorisation holders, the legislative provision laid down in DIR 107b(3)(b) is applied by specifying in the list of EU reference dates, the substances for which PSURs for generic, well-established use, traditional herbal and homeopathic medicinal products are required. This specification is based on the request made by a competent authority in a Member State during the creation or maintenance of the list of EU reference dates and on the basis of concerns relating to pharmacovigilance data or due to the lack of PSURs relating to an active substance.

The harmonised frequency for the submission of the reports and the EU reference dates are determined by the CHMP and/or CMDh after consultation of the PRAC.

The application of the list of EU reference dates for the submission of PSURs for generic, wellestablished use, traditional herbal and homeopathic medicinal products does not undermine the right of a competent authority in a Member State to request the submission of PSURs at any time under the provision laid down in [DIR Art 107c(2) second subparagraph].

For products where PSURs are no longer required to be submitted routinely, it is expected that marketing authorisation holders will continue to evaluate the safety of their products on a regular basis and report any new safety information that impacts on the risk-benefit balance or the product information (See Module VI and Module IX).

Figure VII.4. presents the various potential scenarios as regard the submission of a PSUR for generic, well-established use, traditional herbal and homeopathic medicinal products:

VII.C.3.3.3. Submission of PSURs for fixed dose combination products

Unless otherwise specified in the list of EU reference dates and frequency of submission, if the substance that is the subject of the PSUR is also authorised as a component of a fixed combination medicinal product, the marketing authorisation holder shall either submit a separate PSUR for the combination of active substances authorised for the same marketing authorisation holder with crossreferences to the single-substance PSUR(s), or provide the combination data within one of the singlesubstance PSURs [IR Art 34(7)].

VII.C.3.3.4. Submission of PSURs on demand of a competent authority in a Member State

Marketing authorisation holders shall submit PSURs immediately upon request from a competent authority in a Member State [DIR Art 107c(2)]. To facilitate the EU assessment and avoid duplication of requests, the competent authorities in the Member States should normally make use of the list of EU reference dates to request the submission of PSURs, however in especial circumstances competent authorities in Member States can directly request the submission of a PSUR. When the timeline for submission has not been specified in the request, marketing authorisation holders should submit the PSUR within 90 calendar days of the data lock point.

VII.C.3.4. Criteria used for defining the frequency of submission of PSURs

When deviating from the PSUR submission schedule defined in DIR Art 107c(2)(b), the frequencies of submission of PSURs and the corresponding data lock points should be defined on a risk-based approach by the CHMP where at least one of the marketing authorisations concerned has been granted in accordance with the centralised procedure or by the CMDh otherwise, after consultation with the PRAC.

The following prioritisation criteria should be taken into account when defining the frequency of submission for a given active substance or combination of active substances:

  • information on risks or benefits that may have an impact on the public health;
  • new product for which there is limited safety information available to date (includes pre- and postauthorisation experiences);
  • significant changes to the product (e.g. new indication has been authorised, new pharmaceutical form or route of administration broadening the exposed patient population);
  • vulnerable patient populations/poorly studied patient populations, missing information (e.g. children, pregnant women) while these populations are likely to be exposed in the postauthorisation setting;
  • signal of/potential for misuse, medication error, risk of overdose or dependency;
  • the size of the safety database and exposure to the medicinal product;
  • medicinal products subjected to additional monitoring.

Any change in the criteria listed above for a given active substance or combination of active substances may lead to an amendment of the list of EU reference dates (e.g. increase of the frequency for PSUR submission).

VII.C.3.5. Maintenance of the list of EU reference dates

VII.C.3.5.1. General principles

The maintenance of the list of EU reference dates should facilitate regulatory responsiveness to public health concerns identified within the EU and therefore the list will be subject to changes to reflect the decisions taken (e.g. by the Agency’s committees following signal detection). The information included in the list such as the active substances and combinations of active substances, the frequencies of submission of PSURs and data lock points may need to be updated when considered necessary by the CHMP or CMDh after consultation with the PRAC. Changes to the list may be applied on one of the following grounds:

  • emergence of new information that might have an impact on the risk-benefit balance of the active substances or combinations of active substances, and potentially on public health;
  • any change in the criteria used for the allocation of frequency for PSUR submission and defined under VII.C.3.4.;
  • a request from the marketing authorisation holders as defined under DIR Art 107c(6);
  • active substance newly authorised. Figure VII.5. provides a general overview of the maintenance of the list of EU reference dates and frequency of submission of PSURs:

VII.C.3.5.2. Requests from marketing authorisation holders to amend the list of EU reference dates

Marketing authorisation holders shall be allowed to submit a request to the CHMP or the CMDh, as appropriate, to determine the Union reference dates or to change the frequency of submission of PSURs on one of the following grounds [DIR Art 107c(6)]:

  • for reasons relating to public health;
  • in order to avoid a duplication of the assessment;
  • in order to achieve international harmonisation.

The request and its grounds should be considered by the PRAC and the CHMP if it concerns at least one marketing authorisation granted in accordance with the centralised procedure or the CMDh otherwise, which will either approve or deny the request.

The list will then be amended accordingly when appropriate and published on the European medicines web-portal (see section VII.C.3.6.).

For details about how to submit requests for amendments to the list, refer to the EU reference dates cover note and the related template published on the European medicines web-portal21

VII.C.3.6. Publication of the list

Upon its establishment and adoption by the CHMP and CMDh following PRAC consultation, the list of EU reference dates and frequency of submission of PSURs is published on the European medicines webportal.

In case of amendments, the updated list should be published following its adoption by the CHMP or the CMDh. It is expected to be updated monthly.

VII.C.3.7. Amendment of the marketing authorisation according to the list of EU reference dates

Any changes to the dates and frequencies of submission of PSURs specified in the list take effect six months after the date of the publication on the European medicines web-portal. Where appropriate, marketing authorisation holders shall submit the relevant variation in order to reflect the changes in their marketing authorisation [DIR 107c(6)], unless the marketing authorisation contains a direct cross reference to the list of EU references dates.