Information for marketing authorisation holder

Referral procedures pursuant to Articles 30, 31 and 107i of Directive 2001/83/EC and their national implementation  

A referral procedure consists in reviewing of selected marketing authorisations in order to harmonise the SmPC, PIL and labelling or in order to resolve issues concerning the safety and efficacy of a medicinal product, which are most often identified by the pharmacovigilance system.

In the European legislation, the procedure is laid down in Directive 2001/83/EC of the European Parliament and of the Council on the Community code relating to medicinal products for human use, in the Czech legislation it is referred to in Section 42 of Act No. 378/2007 Coll., on pharmaceuticals and amendments to some other related acts (Act on Pharmaceuticals), as amended.

 

Course of the procedure

The procedure may be initiated by any European Economic Area (EEA) Member State, the European Commission, a marketing authorisation holder or applicant for a marketing authorisation by sending to the European Medicines Agency Secretariat (EMA) a request for the commencement of a referral procedure together with the questions relevant to the given issue. The EMA then informs the EEA Member States of the commencement of the procedure and invites them to prepare a list of concerned medicinal products.

Further information on referral procedures up to the issuance of the European Commission Implementing Decision (“EC Decision”)/Agreement of the Co-ordination group for Mutual Recognition and Decentralised Procedures for human use (“CMDh Agreement”) is available on the EMA website.

The course of individual referral procedures may be followed on the EMA website.

 

European Commission Implementing Decision

Where the scope of the referral procedure includes at least one marketing authorisation granted in accordance with the centralised procedure, the Committee for Medicinal Products for Human Use (“CHMP”) shall, within 30 days of receipt of the recommendation of the Pharmacovigilance Risk Assessment Committee (“PRAC”), consider the recommendation and adopt an opinion on the maintenance, variation, suspension, revocation or refusal of the renewal of the marketing authorisations concerned. Where an urgent adoption of the opinion is necessary, and on the basis of a proposal by its chairman, the CHMP may agree to a shorter deadline. Where the opinion of the CHMP differs from the recommendation of the PRAC, the CHMP shall attach to its opinion a detailed explanation of the scientific grounds for the differences together with the recommendation. On the basis of the opinion of the CHMP, the Commission shall adopt a decision addressed to the Member States concerning the measures to be taken in respect of marketing authorisations that are granted by the Member States.

The European Commission shall issue a binding decision with an annex, taking into account the results of the scientific evaluation. The outcome of the procedure is a variation, maintenance, suspension or revocation of the marketing authorisation of the products that are subject to the referral procedure.

Annex I to the EC Decision shall contain a list of medicinal products subject to the procedure. Where the procedure has been initiated pursuant to Article 30 the list shall only include original medicinal products, however, the obligation to implement the results of the referral procedure also applies to the holders of marketing authorisations for generic medicinal products. The EC Decision usually also lays down the conditions for the implementation of the results of the referral procedure for medicinal products that are not listed in Annex I but meet the criteria for being included in the procedure (e.g. medicinal products of a suitable pharmaceutical form which contain the required active substance but were registered in the course of the referral procedure).

Annex II summarises the scientific conclusions and justification of the variation to the conditions of the marketing authorisation. It briefly states who, when and for what reason initiated the procedure, what studies have been conducted with the given medicinal product so far and what benefits and risks are associated with its use.

If the result of the referral procedure is a marketing authorisation variation, Annex III shall contain the updated text of the SmPC, PIL and labelling.

Where it is necessary, due to concerns over the safety and efficacy of the medicinal product, to set for the marketing authorisation holder the conditions of the marketing authorisation or conditions for lifting the marketing authorisation suspension, such conditions are stated in the final part of the Annex to the EC Decision (usually as Annex IV). The European Commission may impose an obligation to conduct a pharmacokinetic study or post-authorisation safety study to assess all possible risks, to submit a risk management plan, provide the users/healthcare professionals with information on the correct use of the medicinal product and other obligations.

 

The EC Decisions are published on the European Commission website.

Newly issued EC Decisions (for the past 6 months).

 

CMDh Agreement

Where the scope of the referral procedure does not include any marketing authorisation granted in accordance with the centralised procedure, the CMDh shall, within 30 days of receipt of the recommendation of the PRAC, consider the recommendation and reach a position on the maintenance, variation, suspension or revocation of the marketing authorisations concerned, including a timetable for the implementation of the agreed position.

If, within the CMDh, the Member States represented reach agreement on the action to be taken by consensus, the chairman shall record the agreement and send it to the marketing authorisation holders concerned and the Member States. The Member States shall adopt necessary measures to maintain, vary, suspend, revoke or refuse renewal of the marketing authorisations concerned in accordance with the implementation timetable determined in the agreement.

In the event that a variation to the marketing authorisation is agreed upon, the marketing authorisation holder of the medicinal products concerned shall submit to the national competent authorities an appropriate application for a variation to the marketing authorisation, including an updated text of the SmPC, PIL and labelling within the determined timetable for implementation.

 

The CMDh Agreements contain similar Annexes as the EC Decisions, including the translation of updated texts of the SmPC, PIL and labelling of the medicinal product and are published on the European Medicines Agency's website.

 

National implementation of the European Commission Implementing Decision

The information on the procedures to be adopted following the issuance of the EC Decision in order to implement the results of the referral procedure is available on the CMDh website.

 

 

Article 30

This is a harmonisation referral, whose aim is to address divergences between national decisions on marketing authorisation of medicinal products. This referral procedure is applied where EEA Member States have adopted different decisions on marketing authorisation of medicinal products and therefore there is a divergence between the texts of the SmPC, PIL and labelling of the medicinal product (sometimes the harmonisation also applies to Module 3 of the marketing authorisation documentation).

 

Implementation of the European Commission Implementing Decision

The outcome of the procedure is usually a variation to the marketing authorisation. 

1) Medicinal products listed in Annex I of the EC Decision = original medicinal products - within 10 days following the issuance of the EC Decision, the marketing authorisation holder shall submit an application for a variation to the marketing authorisation:

  • where the harmonisation affects the texts – variation of type IAIN C.I.1a 
  • where the harmonisation affects the texts and Module 3 – grouped application of type IAIN for variations C.I.1a and B.V.b.1.a

Where nationally authorised original medicinal products are concerned, their marketing authorisations are transferred into MRP status after the submission of the application for a variation to the marketing authorisation.

Where the Czech Republic has been chosen as the Reference Member State and the marketing authorisation holder fails to apply for a marketing authorisation variation within 10 days following the issuance of the EC Decision, the State Institute for Drug Control shall invite the marketing authorisation holder to apply for a variation to the marketing authorisation by means of a request for cooperation.

Where the Czech Republic is a Concerned Member State, this is within the competence of the chosen Reference Member State.

2) Medicinal products not listed in Annex I of the EC Decision – generic medicinal products:

As of 4 August 2013, the submission of applications for variations to the marketing authorisations of nationally authorised medicinal products shall be governed by the same rules as variations relevant to medicinal products authorised through a MRP/DCP. The marketing authorisation holder shall submit an application for a variation to the marketing authorisation within 90 days following the issuance of the EC Decision:

  • where no additional new data are submitted – variation of type IB C.I.1b
  • where additional new data are submitted – variation of type II C.I.1c

Where the medicinal product is nationally authorised or where the Czech Republic is the Reference Member State and the marketing authorisation holder fails to apply for the respective variation within 90 days following the issuance of the EC Decision, the State Institute for Drug Control shall invite the marketing authorisation holder to apply for the variation by means of a request for cooperation.

Where the Czech Republic is a Concerned Member State, the implementation of the EC Decision shall be supervised by the respective Reference Member State.

 

 

Article 31

A referral procedure pursuant to Article 31 is usually initiated due to issues concerning the safety, efficacy and quality of medicinal products. The procedure involves a group of medicinal products containing the same active substance, series of active substances or medicinal products belonging to the same therapeutic group. The outcome of the procedure is usually a variation to the marketing authorisation or a suspension of the marketing authorisation.

 

Implementation of the European Commission Implementing Decision/CMDh Agreement

Where the procedure results in a variation to marketing authorisation, we distinguish between referral procedures pursuant to Article 31(1) and 31(2):

1) the result of a referral procedure pursuant to Article 31(1) is a harmonisation of the entire texts of the SmPC, PIL and labelling and therefore the marketing authorisations of nationally authorised  medicinal products are transferred into MRP status after the submission of the application for a variation (see below).

2) the result of a referral procedure pursuant to Article 31(2) is a harmonisation of selected parts of the texts and therefore the transfer of national marketing authorisations into MRP status is not required.

As of 4 August 2013, the submission of applications for variations to the marketing authorisations of nationally authorised medicinal products shall be governed by the same rules as variations relevant to medicinal products authorised through a MRP/DCP. After the referral pursuant to Article 31(1) or 31(2) the marketing authorisation holder shall submit an application for a variation to the marketing authorisation within 10 days following the issuance of the EC Decision or according to the timetable for implementation as appended to the CMDh Agreement:

  • where the harmonisation affects the texts – variation of type IAIN or IB C.I.1a

Where the medicinal product is nationally authorised or where the Czech Republic is the Reference Member State and the marketing authorisation holder fails to apply for the respective variation within 10 days following the issuance of the EC Decision or within the timetable for implementation as appended to the CMDh Agreement, the State Institute for Drug Control shall invite the marketing authorisation holder to apply for the variation by means of a request for cooperation.

Where the Czech Republic is a Concerned Member State, the implementation of the EC Decision shall be supervised by the respective Reference Member State.

  

 

Article 107i

This is a safety referral procedure which is applied upon the evaluation of pharmacovigilance signals. The referral procedure pursuant to Article 107i is the most serious one. The result of the procedure is usually a variation to the marketing authorisation, suspension or revocation of the marketing authorisation. In exceptional cases, where urgent action is necessary to protect public health, the temporary measures can be taken before the issuance of a final EC decision/CMDh Agreement.

 

Implementation of the European Commission Implementing Decision/CMDh Agreement

Where the procedure results in a variation to the marketing authorisation, the marketing authorisation holder shall submit an application for a variation to the marketing authorisation of type IAIN or IB C.I.1a within 10 days following the issuance of the EC Decision or according to the timetable for implementation as appended to the CMDh Agreement.  As of 4 August 2013, the submission of applications for variations to the marketing authorisations of nationally authorised medicinal products shall be governed by the same rules as variations relevant to medicinal products authorised through a MRP/DCP.

Where the medicinal product is nationally authorised or where the Czech Republic is the Reference Member State and the marketing authorisation holder fails to apply for the respective variation within 10 days following the issuance of the EC Decision or within the timetable for implementation as appended to the CMDh Agreement, the State Institute for Drug Control shall invite the marketing authorisation holder to apply for the variation by means of a request for cooperation.

Where the Czech Republic is a Concerned Member State, the implementation of the EC Decision/CMDh Agreement shall be supervised by the respective Reference Member State.

 

Request for cooperation

In the case that the respective application for a variation to the marketing authorisation has not been submitted in the required time limit, the State Institute for Drug Control shall invite the marketing authorisation holder to apply for the required variation to the marketing authorisation by means of a request for cooperation. The time limit for submission of the application for a variation to the marketing authorisation is 10 days following the issuance of the EC Decision or according to the timetable for implementation as appended to the CMDh Agreement (except for generic medicinal products subject to a referral pursuant to Article 30, where a 90-day time limit is applied). The marketing authorisation holder’s obligation to cooperate with the State Institute for Drug Control and the obligation to submit an application for a variation to the marketing authorization is laid down in Section 33, paragraph 1 and 3 of the Act on Pharmaceuticals. Any failure to comply with these obligations shall be considered an administrative offence pursuant to Section 105, paragraph 5 (b) of the Act on Pharmaceuticals, for which a fine may be imposed upon the marketing authorisation holder in the amount of up to CZK 20,000,000.00 (Section 107, paragraph 1 (e) of the Act on Pharmaceuticals).

 

Suspension and revocation of a marketing authorisation on the basis of a European Commission Implementing Decision/CMDh Agreement

Where a referral procedure results in a suspension or revocation of the marketing authorisation, the State Institute for Drug Control initiates an ex officio administrative procedure on a suspension or revocation of the marketing authorisation involving the marketing authorisation holders of all medicinal products defined in the EC Decision/CMDh Agreement (i.e. also in the case that the Czech Republic is a Concerned Member State). 

 

Department of Administrative Support
26. 8. 2013