Regulation (EC) No 726/2004 of the European Parliament and of the Council of 31 March 2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency (Text with EEA relevance)

TITLE I

DEFINITIONS AND SCOPE

Article 1

The purpose of this Regulation is to lay down Union procedures for the authorisation, supervision and pharmacovigilance of medicinal products for human use and to establish a European Medicines Agency (‘the Agency’) which shall carry out the tasks relating to medicinal products for human use and veterinary medicinal products that are laid down in this Regulation and other relevant Union legislation.

The provisions of this Regulation shall not affect the powers of Member States' authorities as regards setting the prices of medicinal products or their inclusion in the scope of the national health system or social security schemes on the basis of health, economic and social conditions. In particular, Member States shall be free to choose from the particulars shown in the marketing authorisation those therapeutic indications and pack sizes which will be covered by their social security bodies.

Article 2

The definitions laid down in Article 1 of Directive 2001/83/EC shall apply for the purposes of this Regulation.

As a consequence, in this Regulation, the terms, ‘medicinal product’ and ‘medicinal product for human use’ mean a medicinal product as defined in point (2) of Article 1 of Directive 2001/83/EC.

In addition, the following definitions shall apply for the purposes of this Regulation:

(1) ‘veterinary medicinal product’ means a medicinal product as defined in point (1) of Article 4 of Regulation (EU) 2019/6 of the European Parliament and of the Council (¹) ;

(2) ‘antimicrobial’ means an antimicrobial as defined in point (12) of Article 4 of Regulation (EU) 2019/6.

The holder of a marketing authorisation for medicinal products covered by this Regulation must be established in the  Union. The holder shall be responsible for the placing on the market of those medicinal products, whether he does it himself or via one or more persons designated to that effect.

Article 3

Any medicinal product not appearing in Annex I may be granted a marketing authorisation by the Union in accordance with this Regulation, if:

(a) the medicinal product contains an active substance which, on 20 May 2004, was not authorised in the Union; or

(b) the applicant shows that the medicinal product constitutes a significant therapeutic, scientific or technical innovation or that the granting of authorisation in accordance with this Regulation is in the interest of patients' health at Union level.

A generic medicinal product of a reference medicinal product authorised by the Union may be authorised by the competent authorities of the Member States in accordance with Directive 2001/83/EC under the following conditions:

(a) the application for authorisation is submitted in accordance with Article 10 of Directive 2001/83/EC;

(b) the summary of the product characteristics is in all relevant respects consistent with that of the medicinal product authorised by the  Union except for those parts of the summary of product characteristics referring to indications or dosage forms which were still covered by patent law at the time when the generic medicine was marketed; and

(c) the generic medicinal product is authorised under the same name in all the Member States where the application has been made. For the purposes of this provision, all the linguistic versions of the INN (international non-proprietary name) shall be considered to be the same name.

Article 4

TITLE II

AUTHORISATION AND SUPERVISION OF MEDICINAL PRODUCTS FOR HUMAN USE

Chapter 1

Submission and examination of applications — Authorisations

Article 5

Article 6

The application shall be accompanied by the fee payable to the Agency for the examination of the application.

In the case of a medicinal product for human use containing or consisting of genetically modified organisms within the meaning of Article 2 of Directive 2001/18/EC, the application shall be accompanied by:

(a) a copy of the competent authorities' written consent to the deliberate release into the environment of the genetically modified organisms for research and development purposes where provided for in Part B of Directive 2001/18/EC or in Part B of Council Directive 90/220/EEC of 23 April 1990 on the deliberate release into the environment of genetically modified organisms (²);

(b) the complete technical dossier supplying the information required by Annexes III and IV to Directive 2001/18/EC;

(c) the environmental risk assessment in accordance with the principles set out in Annex II to Directive 2001/18/EC; and

(d) the results of any investigations performed for the purposes of research or development.

Articles 13 to 24 of Directive 2001/18/EC shall not apply to medicinal products for human use containing or consisting of genetically modified organisms.

The duration of the analysis of the scientific data in the file concerning the application for marketing authorisation must be at least 80 days, except in cases where the rapporteur and co-rapporteur declare that they have completed their assessment before that time.

On the basis of a duly reasoned request, the said Committee may call for the duration of the analysis of the scientific data in the file concerning the application for marketing authorisation to be extended.

In the case of a medicinal product for human use containing or consisting of genetically modified organisms, the opinion of the said Committee shall respect the environmental safety requirements laid down by Directive 2001/18/EC. During the process of evaluating applications for marketing authorisations for medicinal products for human use containing or consisting of genetically modified organisms, the rapporteur shall carry out necessary consultations of bodies that the  Union or Member States have set up in accordance with Directive 2001/18/EC.

Article 7

In order to prepare its opinion, the Committee for Medicinal Products for Human Use:

(a) shall verify that the particulars and documents submitted in accordance with Article 6 comply with the requirements of Directive 2001/83/EC, and shall examine whether the conditions specified in this Regulation for granting a marketing authorisation are satisfied;

(b) may request that an Official Medicines Control Laboratory or a laboratory that a Member State has designated for that purpose test the medicinal product for human use, its starting materials and, if need be, its intermediate products or other constituent materials in order to ensure that the control methods employed by the manufacturer and described in the application documents are satisfactory;

(c) may request that the applicant supplement the particulars accompanying the application within a specific time period. Where the said Committee avails itself of this option, the time-limit laid down in Article 6(3), first subparagraph, shall be suspended until such time as the supplementary information requested has been provided. Likewise, this time-limit shall be suspended for the time allowed for the applicant to prepare oral or written explanations.

Article 8

The inspection shall be carried out within the time-limit laid down in the first subparagraph of Article 6(3) by inspectors from the Member State holding the appropriate qualifications; they may be accompanied by a rapporteur or an expert appointed by the Committee.

Article 9

The Agency shall forthwith inform the applicant if the opinion of the Committee for Medicinal Products for Human Use is that:

(a) the application does not satisfy the criteria for authorisation set out in this Regulation;

(b) the summary of the product characteristics proposed by the applicant needs to be amended;

(c) the labelling or package leaflet of the product is not in compliance with Title V of Directive 2001/83/EC;

(d) the authorisation needs to be granted subject to the conditions provided for in Article 14(8) and Article 14-a.

Within 60 days following receipt of the grounds for the request, the said Committee shall re-examine its opinion in accordance with the conditions laid down in the fourth subparagraph of Article 62(1). The reasons for the conclusion reached shall be annexed to the final opinion.

If an opinion is favourable to the granting of the relevant authorisation to place the medicinal product concerned on the market, the following documents shall be annexed to the opinion:

(a) a draft summary of the product characteristics, as referred to in Article 11 of Directive 2001/83/EC;

(aa) a recommendation on the frequency of submission of periodic safety update reports;

(b) details of any conditions or restrictions which should be imposed on the supply or use of the medicinal product concerned, including the conditions under which the medicinal product may be made available to patients, in accordance with the criteria laid down in Title VI of Directive 2001/83/EC;

(c) details of any recommended conditions or restrictions with regard to the safe and effective use of the medicinal product;

(ca) details of any recommended measures for ensuring the safe use of the medicinal product to be included in the risk management system;

(cb) if appropriate, details of any recommended obligation to conduct post-authorisation safety studies or to comply with obligations on the recording or reporting of suspected adverse reactions which are stricter than those referred to in Chapter 3;

(cc) if appropriate, details of any recommended obligation 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 10b while taking into account the scientific guidance referred to in Article 108a of Directive 2001/83/EC;

(d) the draft text of the labelling and package leaflet proposed by the applicant, presented in accordance with Title V of Directive 2001/83/EC;

(e) the assessment report as regards the results of the pharmaceutical and pre-clinical tests and of the clinical trials, and as regards the risk management system and the pharmacovigilance system for the medicinal product concerned.

Article 10

Where a draft decision envisages the granting of a marketing authorisation, it shall include or make reference to the documents mentioned in points (a) to (d) of Article 9(4).

Where a draft decision envisages the granting of a marketing authorisation subject to the conditions referred to in points (c), (ca), (cb), or (cc) of Article 9(4), it shall lay down deadlines for the fulfilment of the conditions, where necessary.

Where the draft decision differs from the opinion of the Agency, the Commission shall attach a detailed explanation of the reasons for the differences.

The draft decision shall be forwarded to Member States and the applicant.

The adjustments shall provide that:

(a) the opinion of the said Standing Committee is to be given in writing;

(b) Member States shall have 22 days to forward their written observations on the draft decision to the Commission. However, if a decision has to be taken urgently, a shorter time-limit may be set by the Chairman according to the degree of urgency involved. This time-limit shall not, otherwise than in exceptional circumstances, be shorter than 5 days;

(c) Member States may request in writing that the draft decision referred to in paragraph 1 be discussed by a plenary meeting of the said Standing Committee, stating their reasons in detail.

Article 10a

After the granting of a marketing authorisation, the Agency 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 Agency 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 10b while taking into account the scientific guidance referred to in Article 108a of Directive 2001/83/EC.

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.

Article 10b

Article 11

If an applicant withdraws an application for a marketing authorisation submitted to the Agency before an opinion has been given on the application, the applicant shall communicate its reasons for doing so to the Agency. The Agency shall make this information publicly accessible and shall publish the assessment report, if available, after deletion of all information of a commercially confidential nature.

Article 12

Authorisation shall likewise be refused if particulars or documents provided by the applicant in accordance with Article 6 are incorrect or if the labelling and package leaflet proposed by the applicant are not in accordance with Title V of Directive 2001/83/EC.

Article 13

Authorised medicinal products for human use shall be entered in the  Union Register of Medicinal Products and shall be given a number, which shall appear on the packaging.

The European Public Assessment Report (EPAR) 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.

The marketing authorisation holder shall notify the Agency if the product ceases to be placed on the market of a Member State, either temporarily or permanently. 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 Agency of the reasons for such action in accordance with Article 14b.

Upon request by the Agency, particularly in the context of pharmacovigilance, the marketing authorisation holder shall provide the Agency with all data relating to the volume of sales of the medicinal product at  Union level, broken down by Member State, and any data in the holder's possession relating to the volume of prescriptions.

Article 14

To this end, the marketing authorisation holder shall provide the Agency 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 Chapter 3, 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.

If the Committee for Medicinal Products for Human Use accepts the request, the time-limit laid down in Article 6(3), first subparagraph, shall be reduced to 150 days.

Article 14-a

The Commission is empowered to adopt delegated acts in accordance with Article 87b in order to supplement this Regulation by specifying:

(a) the categories of medicinal products to which paragraph 1 of this Article applies; and

(b) the procedures and requirements for granting a marketing authorisation pursuant to this Article and for its renewal.

Article 14a

The marketing authorisation holder shall incorporate any conditions referred to in points (c), (ca), (cb) and (cc) of Article 9(4) or in Article 10a, or in Article 14(7) and (8) in his risk management system.

Article 14b

Article 15

The granting of authorisation shall not affect the civil or criminal liability of the manufacturer or of the holder of the marketing authorisation pursuant to the applicable national law in Member States.

Chapter 2

Supervision and penalties

Article 16

In particular, the marketing authorisation holder shall forthwith inform the Agency and the Commission 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.

The Agency 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 seven days after receipt of the request.

Article 16a

The Commission is empowered to adopt delegated acts in accordance with Article 87b in order to supplement this Regulation 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.

Article 16b

A marketing authorisation may be transferred to a new marketing authorisation holder. Such a transfer shall not be considered to be a variation. The transfer shall be subject to prior approval by the Commission, following the submission of an application for the transfer to the Agency.

The Commission is empowered to adopt delegated acts in accordance with Article 87b in order to supplement this Regulation by establishing procedures for the examination of applications to the Agency for the transfer of marketing authorisations.

Article 17

The applicant or the holder of a marketing authorisation shall be responsible for the accuracy of the documents and of the data submitted.

Article 18

A Member State may request assistance from another Member State or from the Agency.

Article 19

The supervisory authorities for pharmacovigilance shall be responsible for verifying on behalf of the Union that the marketing authorisation holder for the medicinal product satisfies the pharmacovigilance requirements laid down in Titles IX and XI of Directive 2001/83/EC. They may, if this is considered necessary, conduct pre-authorisation inspections to verify the accuracy and successful implementation of the pharmacovigilance system as it has been described by the applicant in support of his application.

The inspection shall be undertaken by inspectors from the Member States who possess the appropriate qualifications. They may be accompanied by a rapporteur or expert appointed by the Committee referred to in paragraph 2. The report of the inspectors shall be made available electronically to the Commission, the Member States and the Agency.

Article 20