TITLE III

PLACING ON THE MARKET
CHAPTER 3

Procedures relevant to the marketing authorization
Article 17
1
Member States shall take all appropriate measures to ensure that the procedure for granting a marketing authorisation for medicinal products is completed within a maximum of 210 days after the submission of a valid application.
Applications for marketing authorisations in two or more Member States in respect of the same medicinal product shall be submitted in accordance with
Articles 28
to 39.
2
Where a Member State notes that another marketing authorisation application for the same medicinal product is being examined in another Member State, the Member State concerned shall decline to assess the application and shall advise the applicant that
Articles 28
to 39 apply.
Article 18
Where a Member State is informed in accordance with Article 8(3)(1) that another Member State has authorised a medicinal product which is the subject of a marketing authorisation application in the Member State concerned, it shall reject the application unless it was submitted in compliance with
Articles 28
to 39.
Article 19
In order to examine the application submitted in accordance with Articles 8, 10, 10a, 10b and 10c, the competent authority of the Member State:
1. must verify whether the particulars submitted in support of the application comply with the said Articles 8, 10, 10a, 10b and 10c and examine whether the conditions for issuing an authorization to place medicinal products on the market (marketing authorization) are complied with.
2. may submit the medicinal product, its starting materials and, if need be, its intermediate products or other constituent materials, for testing by an Official Medicines Control Laboratory or a laboratory that a Member State has designated for that purpose in order to ensure that the control methods employed by the manufacturer and described in the particulars accompanying the application in accordance with Article 8(3)(h) are satisfactory.
3. may, where appropriate, require the applicant to supplement the particulars accompanying the application in respect of the items listed in the Articles 8(3), 10, 10a, 10b and 10c. Where the competent authority avails itself of this option, the time limits laid down in Article 17 shall be suspended until such time as the supplementary information required has been provided. Likewise, these time limits shall be suspended for the time allowed the applicant, where appropriate, for giving oral or written explanation.
Article 20
Member States shall take all appropriate measures to ensure that:
1. the competent authorities verify that manufacturers and importers of medicinal products coming from third countries are able to carry out manufacture in compliance with the particulars supplied pursuant to Article 8(3)(d), and/or to carry out controls according to the methods described in the particulars accompanying the application in accordance with Article 8(3)(h);
2. the competent authorities may allow manufacturers and importers of medicinal products coming from third countries, in justifiable cases, to have certain stages of manufacture and/or certain of the controls referred to in (a) carried out by third parties; in such cases, the verifications by the competent authorities shall also be made in the establishment designated.
Article 21
1
When the marketing authorization is issued, the holder shall be informed, by the competent authorities of the Member State concerned, of the summary of the product characteristics as approved by it.
2
The competent authorities shall take all necessary measures to ensure that the information given in the summary is in conformity with that accepted when the marketing authorization is issued or subsequently.
3
The national competent authorities shall, without delay, make publicly available the marketing authorisation together with the package leaflet, the summary of the product characteristics and any conditions established in accordance with Articles 21a, 22 and 22a, together with any deadlines for the fulfilment of those conditions for each medicinal product which they have authorised.
4
The national competent authorities shall draw up an assessment report and make comments on the file as regards the results of the pharmaceutical and pre-clinical tests, the clinical trials, the risk management system and the pharmacovigilance system of the medicinal product concerned. The assessment report shall be updated whenever new information becomes available which is important for the evaluation of the quality, safety or efficacy of the medicinal product concerned.
The national competent authorities shall make the assessment report publicly accessible without delay, together with the reasons for their opinion, after deletion of any information of a commercially confidential nature. The justification shall be provided separately for each indication applied for.
The public assessment report shall include a summary written in a manner that is understandable to the public. The summary shall contain, in particular, a section relating to the conditions of use of the medicinal product.
Article 21a
In addition to the provisions laid down in Article 19, a marketing authorisation for a medicinal product may be granted subject to one or more of the following conditions:
1. to take certain measures for ensuring the safe use of the medicinal product to be included in the risk management system;
2. to conduct post-authorisation safety studies;
3. to comply with obligations on the recording or reporting of suspected adverse reactions which are stricter than those referred to in Title IX;
4. any other conditions or restrictions with regard to the safe and effective use of the medicinal product;
5. the existence of an adequate pharmacovigilance system;
6. to conduct post-authorisation efficacy studies where concerns relating to some aspects of the efficacy of the medicinal product are identified and can be resolved only after the medicinal product has been marketed. Such an obligation to conduct such studies shall be based on the delegated acts adopted pursuant to Article 22b while taking into account the scientific guidance referred to in Article 108a.
The marketing authorisation shall lay down deadlines for the fulfilment of these conditions where necessary.
Article 22
In exceptional circumstances and following consultation with the applicant, the marketing authorisation may be granted subject to certain conditions, in particular relating to the safety of the medicinal product, notification to the national competent authorities of any incident relating to its use, and action to be taken.
The marketing authorisation may be granted only when the applicant can show that he is unable to provide comprehensive data on the efficacy and safety of the medicinal product under normal conditions of use, for objective, verifiable reasons and must be based on one of the grounds set out in Annex I.
Continuation of the marketing authorisation shall be linked to the annual reassessment of these conditions.
Article 22a
1
After the granting of a marketing authorisation, the national competent authority may impose an obligation on the marketing authorisation holder:
a
to conduct a post-authorisation safety study if there are concerns about the risks of an authorised medicinal product. If the same concerns apply to more than one medicinal product, the national competent authority shall, following consultation with the Pharmacovigilance Risk Assessment Committee, encourage the marketing authorisation holders concerned to conduct a joint post-authorisation safety study;
b
to conduct a post-authorisation efficacy study when the understanding of the disease or the clinical methodology indicate that previous efficacy evaluations might have to be revised significantly. The obligation to conduct the post-authorisation efficacy study shall be based on the delegated acts adopted pursuant to Article 22b while taking into account the scientific guidance referred to in Article 108a.
The imposition of such an obligation shall be duly justified, notified in writing, and shall include the objectives and timeframe for submission and conduct of the study.
2
The national competent authority shall provide the marketing authorisation holder with an opportunity to present written observations in response to the imposition of the obligation within a time limit which it shall specify, if the marketing authorisation holder so requests within 30 days of receipt of the written notification of the obligation.
3
On the basis of the written observations submitted by the marketing authorisation holder, the national competent authority shall withdraw or confirm the obligation. Where the national competent authority confirms the obligation, the marketing authorisation shall be varied to include the obligation as a condition of the marketing authorisation and the risk management system shall be updated accordingly.
Article 22b
1
In order to determine the situations in which post-authorisation efficacy studies may be required under Articles 21a and 22a of this Directive, the Commission may adopt, by means of delegated acts in accordance with Article 121a, and subject to the conditions of Articles 121b and 121c, measures supplementing the provisions in Articles 21a and 22a.
2
When adopting such delegated acts, the Commission shall act in accordance with the provisions of this Directive.
Article 22c
1
The marketing authorisation holder shall incorporate any conditions referred to in Articles 21a, 22 or 22a in his risk management system.
2
The Member States shall inform the Agency of the marketing authorisations that they have granted subject to conditions pursuant to Articles 21a, 22 or 22a.
Article 23
1
After a marketing authorisation has been granted, the marketing authorisation holder shall, in respect of the methods of manufacture and control provided for in Article 8(3)(d) and (h), take account of scientific and technical progress and introduce any changes that may be required to enable the medicinal product to be manufactured and checked by means of generally accepted scientific methods.
Those changes shall be subject to the approval of the competent authority of the Member State concerned.
2
The marketing authorisation holder shall forthwith provide the national competent authority with any new information which might entail the amendment of the particulars or documents referred to in Article 8(3), Articles 10, 10a, 10b and 11, or Article 32(5), or Annex I.
In particular, the marketing authorisation holder shall forthwith inform the national competent authority of any prohibition or restriction imposed by the competent authorities of any country in which the medicinal product is marketed and of any other new information which might influence the evaluation of the benefits and risks of the medicinal product concerned. The information shall include both positive and negative results of clinical trials or other studies in all indications and populations, whether or not included in the marketing authorisation, as well as data on the use of the medicinal product where such use is outside the terms of the marketing authorisation.
3
The marketing authorisation holder shall ensure that the product information is kept up to date with the current scientific knowledge, including the conclusions of the assessment and recommendations made public by means of the European medicines web-portal established in accordance with Article 26 of Regulation (EC) No 726/2004.
4
In order to be able to continuously assess the risk-benefit balance, the national competent authority may at any time ask the marketing authorisation holder to forward data demonstrating that the risk-benefit balance remains favourable. The marketing authorisation holder shall answer fully and promptly any such request.
The national competent authority may at any time ask the marketing authorisation holder to submit a copy of the pharmacovigilance system master file. The marketing authorisation holder shall submit the copy at the latest 7 days after receipt of the request.
Article 23a
After a marketing authorisation has been granted, the holder of the authorisation shall inform the competent authority of the authorising Member State of the date of actual marketing of the medicinal product for human use in that Member State, taking into account the various presentations authorised.
If the product ceases to be placed on the market of a Member State, either temporarily or permanently, the marketing authorisation holder shall notify the competent authority of that Member State. Such notification shall, other than in exceptional circumstances, be made no less than two months before the interruption in the placing on the market of the product. The marketing authorisation holder shall inform the competent authority of the reasons for such action in accordance with Article 123(2).
Upon request by the competent authority, particularly in the context of pharmacovigilance, the marketing authorisation holder shall provide the competent authority with all data relating to the volume of sales of the medicinal product, and any data in his possession relating to the volume of prescriptions.
Article 23b
1
Variations shall be classified in different categories depending on the level of risk to public health and the potential impact on the quality, safety and efficacy of the medicinal product concerned. Those categories shall range from changes to terms of the marketing authorisation that have the highest potential impact on the quality, safety or efficacy of the medicinal product, to changes that have no or minimal impact thereon.
2
The procedures for examination of applications for variations shall be proportionate to the risk and impact involved. Those procedures shall range from procedures that allow implementation only after approval based on a complete scientific assessment to procedures that allow immediate implementation and subsequent notification by the marketing authorisation holder to the competent authority.
2a
The Commission is empowered to adopt delegated acts in accordance with Article 121a in order to supplement this Directive by:
a
specifying the categories in which variations shall be classified; and
b
establishing procedures for the examination of applications for variations to the terms of marketing authorisations.
3
When adopting the delegated acts referred to in this Article, the Commission shall endeavour to make possible the submission of a single application for one or more identical changes made to the terms of different marketing authorisations.
4
A Member State may continue to apply national provisions on variations applicable at the time of entry into force of Commission Regulation (EC) No 1234/2008
to marketing authorisations granted before
1 January 1998
to medicinal products authorised only in that Member State. Where a medicinal product subject to national provisions in accordance with this Article is subsequently granted a marketing authorisation in another Member State, Regulation (EC) No 1234/2008 shall apply to that medicinal product from that date.
5
Where a Member State decides to continue to apply national provisions pursuant to paragraph 4, it shall notify the Commission thereof. If a notification has not been made by
20 January 2011
,
Regulation (EC) No 1234/2008
shall apply.
Article 24
1
Without prejudice to paragraphs 4 and 5, a marketing authorisation shall be valid for five years.
2
The marketing authorisation may be renewed after five years on the basis of a re-evaluation of the risk-benefit balance by the competent authority of the authorising Member State.
To this end, the marketing authorisation holder shall provide the national competent authority with a consolidated version of the file in respect of quality, safety and efficacy, including the evaluation of data contained in suspected adverse reactions reports and periodic safety update reports submitted in accordance with Title IX, and information on all variations introduced since the marketing authorisation was granted, at least 9 months before the marketing authorisation ceases to be valid in accordance with paragraph 1.
3
Once renewed, the marketing authorisation shall be valid for an unlimited period, unless the national competent authority decides, on justified grounds relating to pharmacovigilance, including exposure of an insufficient number of patients to the medicinal product concerned, to proceed with one additional five-year renewal in accordance with paragraph 2.
4
Any authorisation which within three years of its granting is not followed by the actual placing on the market of the authorised product in the authorising Member State shall cease to be valid.
5
When an authorised product previously placed on the market in the authorising Member State is no longer actually present on the market for a period of three consecutive years, the authorisation for that product shall cease to be valid.
6
The competent authority may, in exceptional circumstances and on public health grounds grant exemptions from paragraphs 4 and 5. Such exemptions must be duly justified.
Article 25
Authorization shall not affect the civil and criminal liability of the manufacturer and, where applicable, of the marketing authorization holder.
Article 26
1
The marketing authorisation shall be refused if, after verification of the particulars and documents listed in Articles 8, 10, 10a, 10b and 10c, it is clear that:
a
the risk-benefit balance is not considered to be favourable; or
b
its therapeutic efficacy is insufficiently substantiated by the applicant; or
c
its qualitative and quantitative composition is not as declared.
2
Authorisation shall likewise be refused if any particulars or documents submitted in support of the application do not comply with Articles 8, 10, 10a, 10b and 10c.
3
The applicant or the holder of a marketing authorisation shall be responsible for the accuracy of the documents and the data submitted.
Commission Regulation (EC) No 1234/2008 of
24 November 2008
concerning the examination of variations to the terms of marketing authorisations for medicinal products for human use and veterinary medicinal products (
OJ L 334, 12.12.2008, p. 7
).
Substituted by Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use.
Substituted by Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use (Text with EEA relevance).
Inserted by Directive 2004/27/EC of the European Parliament and of the Council of 31 March 2004 amending Directive 2001/83/EC on the Community code relating to medicinal products for human use.
Inserted by Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use (Text with EEA relevance).
Substituted by Directive 2012/26/EU of the European Parliament and of the Council of 25 October 2012 amending Directive 2001/83/EC as regards pharmacovigilance (Text with EEA relevance).
Inserted by Directive 2009/53/EC of the European Parliament and of the Council of 18 June 2009 amending Directive 2001/82/EC and Directive 2001/83/EC, as regards variations to the terms of marketing authorisations for medicinal products (Text with EEA relevance).
Substituted by Regulation (EU) 2019/5 of the European Parliament and of the Council of 11 December 2018 amending Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, Regulation (EC) No 1901/2006 on medicinal products for paediatric use and Directive 2001/83/EC on the Community code relating to medicinal products for human use (Text with EEA relevance).