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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

Type Directive

Publication 2010-12-31

Last updated 2011-01-20

State In force

Department Council of the European Union, European Parliament

Source EUR-Lex

articles 5

Reform history JSON API

(a)for reasons relating to public health; (b)in order to avoid a duplication of the assessment; (c)in order to achieve international harmonisation. Such requests shall be submitted in writing and shall be duly justified. The Committee for Medicinal Products for Human Use or the coordination group shall, following the consultation with the Pharmacovigilance Risk Assessment Committee, shall either approve or deny such requests. Any change in the dates or the frequency of submission of periodic safety update reports shall be made public by the Agency. The marketing authorisation holders shall accordingly submit an application for a variation of the marketing authorisation.

The Agency shall make public a list of Union reference dates and frequency of submission of periodic safety update reports by means of the European medicines web-portal.

Any change to the dates of submission and frequency of periodic safety update reports specified in the marketing authorisation as a result of the application of paragraphs 4, 5 and 6 shall take effect 6 months after the date of such publication.

Article 107d

The national competent authorities shall assess periodic safety update reports to determine whether there are new risks or whether risks have changed or whether there are changes to the risk-benefit balance of medicinal products.

Article 107e

A single assessment of periodic safety update reports shall be performed for medicinal products authorised in more than one Member State and, in the cases of paragraphs 4 to 6 of Article 107c, for all medicinal products containing the same active substance or the same combination of active substances and for which a Union reference date and frequency of periodic safety update reports has been established.

The single assessment shall be conducted by either of the following: (a)a Member State appointed by the coordination group where none of the marketing authorisations concerned has been granted in accordance with the centralised procedure provided for in Chapter 1 of Title II of Regulation (EC) No 726/2004; or (b)a rapporteur appointed by the Pharmacovigilance Risk Assessment Committee, where at least one of the marketing authorisations concerned has been granted in accordance with the centralised procedure provided for in Chapter 1 of Title II of Regulation (EC) No 726/2004. When selecting the Member State in accordance with point (a) of the second subparagraph, the coordination group shall take into account whether any Member State is acting as a reference Member State, in accordance with Article 28(1).

The Member State or rapporteur, as appropriate, shall prepare an assessment report within 60 days of receipt of the periodic safety update report and send it to the Agency and to the Member States concerned. The Agency shall send the report to the marketing authorisation holder.

Within 30 days of receipt of the assessment report, the Member States and the marketing authorisation holder may submit comments to the Agency and to the rapporteur or Member State.

Following the receipt of the comments referred to in paragraph 2, the rapporteur or Member State shall within 15 days update the assessment report taking into account any comments submitted, and forward it to the Pharmacovigilance Risk Assessment Committee. The Pharmacovigilance Risk Assessment Committee shall adopt the assessment report with or without further changes at its next meeting and issue a recommendation. The recommendation shall mention the divergent positions with the grounds on which they are based. The Agency shall include the adopted assessment report and the recommendation in the repository set up under Article 25a of Regulation (EC) No 726/2004 and forward both to the marketing authorisation holder.

Article 107f

Following the assessment of periodic safety update reports, the national competent authorities shall consider whether any action concerning the marketing authorisation for the medicinal product concerned is necessary. They shall maintain, vary, suspend or revoke the marketing authorisation as appropriate.

Article 107g

In the case of a single assessment of periodic safety update reports that recommends any action concerning more than one marketing authorisation in accordance with Article 107e(1) which does not include any marketing authorisation granted in accordance with the centralised procedure provided for in Chapter 1 of Title II of Regulation (EC) No 726/2004, the coordination group shall, within 30 days of receipt of the report of the Pharmacovigilance Risk Assessment Committee, consider the report 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.

In the event of a variation, the marketing authorisation holder shall submit to the national competent authorities an appropriate application for a modification, including an updated summary of product characteristics and package leaflet within the determined timetable for implementation. If an agreement by consensus cannot be reached, the position of the majority of the Member States represented within the coordination group shall be forwarded to the Commission which shall apply the procedure laid down in Articles 33 and 34. Where the agreement reached by the Member States represented within the coordination group or the position of the majority of Member States differs from the recommendation of the Pharmacovigilance Risk Assessment Committee, the coordination group shall attach to the agreement or the majority position a detailed explanation of the scientific grounds for the differences together with the recommendation.

In the case of a single assessment of periodic safety update reports that recommends any action concerning more than one marketing authorisation in accordance with Article 107e(1) which includes at least one marketing authorisation granted in accordance with the centralised procedure provided for in Chapter 1 of Title II of Regulation (EC) No 726/2004, the Committee for Medicinal Products for Human Use shall, within 30 days of receipt of the report of the Pharmacovigilance Risk Assessment Committee, consider the report and adopt an opinion on the maintenance, variation, suspension or revocation of the marketing authorisations concerned, including a timetable for the implementation of the opinion.

Where this opinion of the Committee for Medicinal Products for Human Use differs from the recommendation of the Pharmacovigilance Risk Assessment Committee, the Committee for Medicinal Products for Human Use 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 Committee for Medicinal Products for Human Use referred to in paragraph 3, the Commission shall:

(a)adopt a decision addressed to the Member States concerning the measures to be taken in respect of marketing authorisations granted by the Member States and concerned by the procedure provided for in this section; and (b)where the opinion states that regulatory action concerning the marketing authorisation is necessary, adopt a decision to vary, suspend or revoke the marketing authorisations granted in accordance with the centralised procedure provided for in Regulation (EC) No 726/2004 and concerned by the procedure provided for in this section. Articles 33 and 34 of this Directive shall apply to the adoption of the decision referred to in point (a) of the first subparagraph of this paragraph and to its implementation by the Member States.

Article 10 of Regulation (EC) No 726/2004 shall apply to the decision referred to in point (b) of the first subparagraph of this paragraph. Where the Commission adopts such decision, it may also adopt a decision addressed to the Member States pursuant to Article 127a of this Directive.

Section 3 Signal detection

Article 107h

Regarding medicinal products authorised in accordance with this Directive, national competent authorities in collaboration with the Agency, shall take the following measures:

(a)monitor the outcome of risk minimisation measures contained in risk management plans and of the conditions referred to in Articles 21a, 22 or 22a; (b)assess updates to the risk management system; (c)monitor the data in the Eudravigilance database to determine whether there are new risks or whether risks have changed and whether those risks impact on the risk-benefit balance.

The Pharmacovigilance Risk Assessment Committee shall perform the initial analysis and prioritisation of signals of new risks or risks that have changed or changes to the risk-benefit balance. Where it considers that follow-up action may be necessary, the assessment of those signals and agreement on any subsequent action concerning the marketing authorisation shall be conducted in a timescale commensurate with the extent and seriousness of the issue.

The Agency and national competent authorities and the marketing authorisation holder shall inform each other in the event of new risks or risks that have changed or changes to the risk-benefit balance being detected.

Member States shall ensure that marketing authorisation holders inform the Agency and national competent authorities in the event of new risks or risks that have changed or when changes to the risk-benefit balance have been detected.

Section 4 Urgent Union procedure

Article 107i

A Member State or the Commission, as appropriate, shall initiate the procedure provided for in this section, by informing the other Member States, the Agency and the Commission when urgent action is considered necessary, as a result of the evaluation of data resulting from pharmacovigilance activities, in any of the following cases:

(a)it considers suspending or revoking a marketing authorisation; (b)it considers prohibiting the supply of a medicinal product; (c)it considers refusing the renewal of a marketing authorisation; (d)it is informed by the marketing authorisation holder that, on the basis of safety concerns, he has interrupted the placing on the market of a medicinal product or has taken action to have a marketing authorisation withdrawn, or that he intends to do so; (e)it considers that a new contraindication, a reduction in the recommended dose, or a restriction to the indications is necessary. The Agency shall verify whether the safety concern relates to medicinal products other than the one covered by the information, or whether it is common to all products belonging to the same range or therapeutic class. Where the medicinal product involved is authorised in more than one Member State, the Agency shall without undue delay inform the initiator of the procedure of the outcome of this verification, and the procedures laid down in Articles 107j and 107k shall apply. Otherwise, the safety concern shall be addressed by the Member State concerned. The Agency or the Member State, as applicable, shall make information that the procedure has been initiated available to marketing authorisation holders.

Without prejudice to the provisions of paragraph 1 of this Article, and Articles 107j and 107k, a Member State may, where urgent action is necessary to protect public health, suspend the marketing authorisation and prohibit the use of the medicinal product concerned on its territory until a definitive decision is adopted. It shall inform the Commission, the Agency and the other Member States no later than the following working day of the reasons for its action.

At any stage of the procedure laid down in Articles 107j to 107k, the Commission may request Member States in which the medicinal product is authorised to take temporary measures immediately.

Where the scope of the procedure, as determined in accordance with paragraph 1, includes medicinal products authorised in accordance with Regulation (EC) No 726/2004, the Commission may, at any stage of the procedure initiated under this section, take temporary measures immediately in relation to those marketing authorisations.

The information referred to in this Article may relate to individual medicinal products or to a range of medicinal products or a therapeutic class.

If the Agency identifies that the safety concern relates to more medicinal products than those which are covered by the information or that it is common to all medicinal products belonging to the same range or therapeutic class, it shall extend the scope of the procedure accordingly. Where the scope of the procedure initiated under this Article concerns a range of medicinal products or therapeutic class, medicinal products authorised in accordance with Regulation (EC) No 726/2004 which belong to that range or class shall also be included in the procedure.

At the time of the information referred to in paragraph 1, the Member State shall make available to the Agency all relevant scientific information that it has at its disposal and any assessment by the Member State.

Article 107j

Following receipt of the information referred to in Article 107i(1), the Agency shall publicly announce the initiation of the procedure by means of the European medicines web-portal. In parallel, Member States may publicly announce the initiation on their national medicines web-portals.

The announcement shall specify the matter submitted to the Agency in accordance with Article 107i, and the medicinal products and, where applicable, the active substances concerned. It shall contain information on the right of the marketing authorisation holders, healthcare professionals and the public to submit to the Agency information relevant to the procedure and it shall state how such information may be submitted.

The Pharmacovigilance Risk Assessment Committee shall assess the matter which has been submitted to the Agency in accordance with Article 107i. The rapporteur shall closely collaborate with the rapporteur appointed by the Committee for Medicinal Products for Human Use and the Reference Member State for the medicinal products concerned.

For the purposes of that assessment, the marketing authorisation holder may submit comments in writing. Where the urgency of the matter permits, the Pharmacovigilance Risk Assessment Committee may hold public hearings, where it considers that this is appropriate on justified grounds particularly with regard to the extent and seriousness of the safety concern. The hearings shall be held in accordance with the modalities specified by the Agency and shall be announced by means of the European medicines web-portal. The announcement shall specify the modalities of participation. In the public hearing, due regard shall be given to the therapeutic effect of the medicinal product. The Agency shall, in consultation with the parties concerned, draw up Rules of Procedure on the organisation and conduct of public hearings, in accordance with Article 78 of Regulation (EC) No 726/2004. Where a marketing authorisation holder or another person intending to submit information has confidential data relevant to the subject matter of the procedure, he may request permission to present that data to the Pharmacovigilance Risk Assessment Committee in a non-public hearing.

Within 60 days of the information being submitted, the Pharmacovigilance Risk Assessment Committee shall make a recommendation, stating the reasons on which it is based, having due regard to the therapeutic effect of the medicinal product. The recommendation shall mention the divergent positions and the grounds on which they are based. In the case of urgency, and on the basis of a proposal by its chairman, the Pharmacovigilance Risk Assessment Committee may agree to a shorter deadline. The recommendation shall include any or a combination of the following conclusions:

(a)no further evaluation or action is required at Union level; (b)the marketing authorisation holder should conduct further evaluation of data together with the follow-up of the results of that evaluation; (c)the marketing authorisation holder should sponsor a post-authorisation safety study together with the follow up evaluation of the results of that study; (d)the Member States or marketing authorisation holder should implement risk minimisation measures; (e)the marketing authorisation should be suspended, revoked or not renewed; (f)the marketing authorisation should be varied. For the purposes of point (d) of the first subparagraph, the recommendation shall specify the risk minimisation measures recommended and any conditions or restrictions to which the marketing authorisation should be made subject. Where, in the cases referred to in point (f) of the first subparagraph, it is recommended to change or add information in the summary of product characteristics or the labelling or package leaflet, the recommendation shall suggest the wording of such changed or added information and where in the summary of the product characteristics, labelling or package leaflet such wording should be placed.

Article 107k

Where the scope of the procedure, as determined in accordance with Article 107i(4), does not include any marketing authorisation granted in accordance with the centralised procedure provided for in Chapter 1 of Title II of Regulation (EC) No 726/2004, the coordination group shall, within 30 days of receipt of the recommendation of the Pharmacovigilance Risk Assessment Committee, consider the recommendation and reach a position on the maintenance, variation, suspension, revocation or refusal of the renewal of the marketing authorisation concerned, including a timetable for the implementation of the agreed position. Where an urgent adoption of the position is necessary, and on the basis of a proposal by its chairman, the coordination group may agree to a shorter deadline.

In the event that a variation is agreed upon, the marketing authorisation holder shall submit to the national competent authorities an appropriate application for a variation, including an updated summary of product characteristics and package leaflet within the determined timetable for implementation. If an agreement by consensus cannot be reached, the position of the majority of the Member States represented within the coordination group shall be forwarded to the Commission which shall apply the procedure laid down in Articles 33 and 34. However, by way of derogation from Article 34(1), the procedure referred to in Article 121(2) shall apply. Where the agreement reached by the Member States represented within the coordination group or the position of the majority of the Member States represented within the coordination group differs from the recommendation of the Pharmacovigilance Risk Assessment Committee, the coordination group shall attach to the agreement or majority position a detailed explanation of the scientific grounds for the differences together with the recommendation.

Where the scope of the procedure, as determined in accordance with Article 107i(4), includes at least one marketing authorisation granted in accordance with the centralised procedure provided for in Chapter 1 of Title II of Regulation (EC) No 726/2004, the Committee for Medicinal Products for Human Use shall, within 30 days of receipt of the recommendation of the Pharmacovigilance Risk Assessment Committee, 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 Committee for Medicinal Products for Human Use may agree to a shorter deadline.

Where the opinion of the Committee for Medicinal Products for Human Use differs from the recommendation of the Pharmacovigilance Risk Assessment Committee, the Committee for Medicinal Products for Human Use 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 Committee for Medicinal Products for Human Use referred to in paragraph 3, the Commission shall:

(a)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 and that are subject to the procedure provided for in this section; and (b)where the opinion is that regulatory action is necessary, adopt a decision to vary, suspend, revoke or refuse renewal of the marketing authorisations granted in accordance with Regulation (EC) No 726/2004 and subject to the procedure provided for in this section. Articles 33 and 34 of this Directive shall apply to the adoption of the decision referred to in point (a) of the first subparagraph of this paragraph and to its implementation by the Member States. However, by way of derogation from Article 34(1) of this Directive, the procedure referred to in Article 121(2) thereof shall apply.

Article 10 of Regulation (EC) No 726/2004 shall apply to the decision referred to in point (b) of the first subparagraph of this paragraph. However, by way of derogation from Article 10(2) of that Regulation, the procedure referred to in Article 87(2) thereof shall apply. Where the Commission adopts such decision, it may also adopt a decision addressed to the Member States pursuant to Article 127a of this Directive.

Section 5 Publication of assessments

Article 107l

The Agency shall make public the final assessment conclusions, recommendations, opinions and decisions referred to in Articles 107b to 107k by means of the European medicines web-portal.

CHAPTER 4 Supervision of post-authorisation safety studies

Article 107m

This Chapter applies to non-interventional post-authorisation safety studies which are initiated, managed or financed by the marketing authorisation holder voluntarily or pursuant to obligations imposed in accordance with Articles 21a or 22a, and which involve the collection of safety data from patients or healthcare professionals.

This Chapter is without prejudice to national and Union requirements for ensuring the well-being and rights of participants in non-interventional post-authorisation safety studies.

The studies shall not be performed where the act of conducting the study promotes the use of a medicinal product.

Payments to healthcare professionals for participating in non-interventional post-authorisation safety studies shall be restricted to the compensation for time and expenses incurred.

The national competent authority may require the marketing authorisation holder to submit the protocol and the progress reports to the competent authorities of the Member States in which the study is conducted.

The marketing authorisation holder shall send the final report to the competent authorities of the Member States in which the study was conducted within 12 months of the end of data collection.

While a study is being conducted, the marketing authorisation holder shall monitor the data generated and consider its implications for the risk-benefit balance of the medicinal product concerned.

Any new information which might influence the evaluation of the risk-benefit balance of the medicinal product shall be communicated to the competent authorities of the Member State in which the medicinal product has been authorised in accordance with Article 23. The obligation laid down in the second subparagraph is without prejudice to the information on the results of studies that the marketing authorisation holder shall make available by means of the periodic safety update reports as laid down in Article 107b.

Articles 107n to 107q shall apply exclusively to studies referred to in paragraph 1 which are conducted pursuant to an obligation imposed in accordance with Articles 21a or 22a.

Article 107n

Before a study is conducted, the marketing authorisation holder shall submit a draft protocol to the Pharmacovigilance Risk Assessment Committee, except for studies to be conducted in only one Member State that requests the study according to Article 22a. For such studies, the marketing authorisation holder shall submit a draft protocol to the national competent authority of the Member State in which the study is conducted.

Within 60 days of the submission of the draft protocol the national competent authority or the Pharmacovigilance Risk Assessment Committee, as appropriate, shall issue:

(a)a letter endorsing the draft protocol; (b)a letter of objection, which shall set out in detail the grounds for the objection, in any of the following cases: (i)it considers that the conduct of the study promotes the use of a medicinal product; (ii)it considers that the design of the study does not fulfil the study objectives; or (c)a letter notifying the marketing authorisation holder that the study is a clinical trial falling under the scope of Directive 2001/20/EC.

The study may commence only when the written endorsement from the national competent authority or the Pharmacovigilance Risk Assessment Committee, as appropriate, has been issued.

Where a letter of endorsement as referred to in paragraph 2(a) has been issued, the marketing authorisation holder shall forward the protocol to the competent authorities of the Member States in which the study is to be conducted and may thereafter commence the study according to the endorsed protocol.

Article 107o

After a study has been commenced, any substantial amendments to the protocol shall be submitted, before their implementation, to the national competent authority or to the Pharmacovigilance Risk Assessment Committee, as appropriate. The national competent authority or the Pharmacovigilance Risk Assessment Committee, as appropriate, shall assess the amendments and inform the marketing authorisation holder of its endorsement or objection. Where applicable, the marketing authorisation holder shall inform Member States in which the study is conducted.

Article 107p

Upon completion of the study, a final study report shall be submitted to the national competent authority or the Pharmacovigilance Risk Assessment Committee within 12 months of the end of data collection unless a written waiver has been granted by the national competent authority or the Pharmacovigilance Risk Assessment Committee, as appropriate.

The marketing authorisation holder shall evaluate whether the results of the study have an impact on the marketing authorisation and shall, if necessary, submit to the national competent authorities an application to vary the marketing authorisation.

Together with the final study report, the marketing authorisation holder shall electronically submit an abstract of the study results to the national competent authority or the Pharmacovigilance Risk Assessment Committee.

Article 107q

Based on the results of the study and after consultation of the marketing authorisation holder, the Pharmacovigilance Risk Assessment Committee may make recommendations concerning the marketing authorisation, stating the reasons on which they are based. The recommendations shall mention the divergent positions and the grounds on which they are based.

When recommendations for the variation, suspension or revocation of the marketing authorisation are made for a medicinal product authorised by the Member States pursuant to this Directive, the Member States represented within the coordination group shall agree a position on the matter taking into account the recommendation referred to in paragraph 1 and including a timetable for the implementation of the agreed position.

If, within the coordination group, 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 holder and the Member States. The Member States shall adopt necessary measures to vary, suspend or revoke the marketing authorisation concerned in accordance with the implementation timetable determined in the agreement. In the event that a variation is agreed upon, the marketing authorisation holder shall submit to the national competent authorities an appropriate application for a variation, including an updated summary of product characteristics and package leaflet within the determined timetable for implementation. The agreement shall be made public on the European medicines web-portal established in accordance with Article 26 of Regulation (EC) No 726/2004. If an agreement by consensus cannot be reached, the position of the majority of the Member States represented within the coordination group shall be forwarded to the Commission, which shall apply the procedure laid down in Articles 33 and 34. Where the agreement reached by the Member States represented within the coordination group or the position of the majority of Member States differs from the recommendation of the Pharmacovigilance Risk Assessment Committee, the coordination group shall attach to the agreement or majority position a detailed explanation of the scientific grounds for the differences together with the recommendation.

CHAPTER 5 Implementation, Delegation and Guidance

Article 108

In order to harmonise the performance of the pharmacovigilance activities provided for in this Directive, the Commission shall adopt implementing measures in the following areas for which pharmacovigilance activities are provided for in Article 8(3), and in Articles 101, 104, 104a, 107, 107a, 107b, 107h, 107n and 107p: (a)the content and maintenance of the pharmacovigilance system master file kept by the marketing authorisation holder; (b)the minimum requirements for the quality system for the performance of pharmacovigilance activities by the national competent authorities and the marketing authorisation holder; (c)the use of internationally agreed terminology, formats and standards for the performance of pharmacovigilance activities; (d)the minimum requirements for the monitoring of data in the Eudravigilance database to determine whether there are new risks or whether risks have changed; (e)the format and content of the electronic transmission of suspected adverse reactions by Member States and the marketing authorisation holder; (f)the format and content of electronic periodic safety update reports and risk management plans; (g)the format of protocols, abstracts and final study reports for the post-authorisation safety studies. Those measures shall take account of the work on international harmonisation carried out in the area of pharmacovigilance and shall, where necessary, be revised to take account of technical and scientific progress. Those measures shall be adopted in accordance with the regulatory procedure referred to in Article 121(2).

Article 108a

In order to facilitate the performance of pharmacovigilance activities within the Union, the Agency shall, in cooperation with competent authorities and other interested parties, draw up: (a)guidance on good pharmacovigilance practices for both competent authorities and marketing authorisation holders; (b)scientific guidance on post-authorisation efficacy studies.

Article 108b

The Commission shall make public a report on the performance of pharmacovigilance tasks by the Member States on 21 July 2015 at the latest and then every 3 years thereafter.’.

21.Article 111 is amended as follows: (a)paragraph 1 is amended as follows: (i)the first subparagraph is replaced by the following: ‘The competent authority of the Member State concerned shall, in cooperation with the Agency, ensure that the legal requirements governing medicinal products are complied with, by means of inspections, if necessary unannounced, and, where appropriate, by asking an Official Medicines Control Laboratory or a laboratory designated for that purpose to carry out tests on samples. This cooperation shall consist in sharing information with the Agency on both inspections that are planned and that have been conducted. Member States and the Agency shall cooperate in the coordination of inspections in third countries.’; (ii)in the fifth subparagraph, point (d) is replaced by the following: ‘(d)inspect the premises, records, documents and pharmacovigilance system master file of the marketing authorisation holder or any firms employed by the marketing authorisation holder to perform the activities described in Title IX.’; (b)paragraph 3 is replaced by the following: ‘3. After every inspection referred to in paragraph 1, the competent authority shall report on whether the inspected entity complies with the principles and guidelines of good manufacturing practice and good distribution practices referred to in Articles 47 and 84, or whether the marketing authorisation holder complies with the requirements laid down in Title IX. The competent authority which carried out the inspection shall communicate the content of those reports to the inspected entity. Before adopting the report, the competent authority shall give the inspected entity concerned the opportunity to submit comments.’; (c)paragraph 7 is replaced by the following: ‘7. If the outcome of the inspection as referred to in points (a), (b) and (c) of paragraph 1 or the outcome of an inspection of a distributor of medicinal products or active substances or a manufacturer of excipients used as starting materials is that the inspected entity does not comply with the legal requirements and/or the principles and guidelines of good manufacturing practice or good distribution practices as provided for by Union law, the information shall be entered in the Union database as provided for in paragraph 6.’; (d)the following paragraph is added: ‘8. If the outcome of the inspection referred to in paragraph 1(d) is that the marketing authorisation holder does not comply with the pharmacovigilance system as described in the pharmacovigilance system master file and with Title IX, the competent authority of the Member State concerned shall bring the deficiencies to the attention of the marketing authorisation holder and give him the opportunity to submit comments. In such case the Member State concerned shall inform the other Member States, the Agency and the Commission. Where appropriate, the Member State concerned shall take the necessary measures to ensure that a marketing authorisation holder is subject to effective, proportionate and dissuasive penalties.’.

22.Article 116 is replaced by the following: ‘Article 116 The competent authorities shall suspend, revoke or vary a marketing authorisation if the view is taken that the medicinal product is harmful or that it lacks therapeutic efficacy, or that the risk-benefit balance is not favourable, or that its qualitative and quantitative composition is not as declared. Therapeutic efficacy shall be considered to be lacking when it is concluded that therapeutic results cannot be obtained from the medicinal product. A marketing authorisation may also be suspended, revoked or varied where the particulars supporting the application as provided for in Articles 8, 10, 10a, 10b, 10c or 11 are incorrect or have not been amended in accordance with Article 23, or where any conditions referred to in Articles 21a, 22 or 22a have not been fulfilled or where the controls referred to in Article 112 have not been carried out.’.

23.Article 117 is amended as follows: (a)paragraph 1 is amended as follows: (i)point (a) is replaced by the following: ‘(a)the medicinal product is harmful; or’; (ii)point (c) is replaced by the following: ‘(c)the risk-benefit balance is not favourable; or’; (b)the following paragraph is added: ‘3. The competent authority may, for a medicinal product for which the supply has been prohibited or which has been withdrawn from the market in accordance with paragraphs 1 and 2, in exceptional circumstances during a transitional period allow the supply of the medicinal product to patients who are already being treated with the medicinal product.’.

24.The following Articles are inserted: ‘Article 121a

The power to adopt the delegated acts referred to in Article 22b shall be conferred on the Commission for a period of 5 years from 20 January 2011. The Commission shall draw up a report in respect of the delegated powers not later than 6 months before the end of the 5 year period. The delegation of powers shall be automatically extended for periods of an identical duration, unless the European Parliament or the Council revokes it in accordance with Article 121b.

As soon as it adopts a delegated act, the Commission shall notify it simultaneously to the European Parliament and to the Council.

The power to adopt delegated acts is conferred on the Commission subject to the conditions laid down in Articles 121b and 121c.

Article 121b

The delegation of powers referred to in Article 22b may be revoked at any time by the European Parliament or by the Council.

The institution which has commenced an internal procedure for deciding whether to revoke the delegation of powers shall endeavour to inform the other institution and the Commission within a reasonable time before the final decision is taken, indicating the delegated powers which could be subject to revocation and possible reasons for a revocation.

The decision of revocation shall put an end to the delegation of the powers specified in that decision. It shall take effect immediately or at a later date specified therein. It shall not affect the validity of the delegated acts already in force. It shall be published in the Official Journal of the European Union.

Article 121c

The European Parliament or the Council may object to a delegated act within a period of 2 months from the date of notification.

At the initiative of the European Parliament or the Council that period shall be extended by 2 months.

If, on expiry of the period referred to in paragraph 1, neither the European Parliament nor the Council has objected to the delegated act, it shall be published in the Official Journal of the European Union and shall enter into force on the date stated therein.

The delegated act may be published in the Official Journal of the European Union and enter into force before the expiry of that period if the European Parliament and the Council have both informed the Commission of their intention not to raise objections.

If either the European Parliament or the Council objects to the delegated act within the period referred to in paragraph 1, it shall not enter into force. The institution which objects shall state the reasons for objecting to the delegated act.’.

25.Article 122(2) is replaced by the following: ‘2. Upon reasoned request, Member States shall send electronically the reports referred to in Article 111(3) to the competent authorities of another Member State or to the Agency.’.

26.Article 123(4) is replaced by the following: ‘4. The Agency shall make public annually a list of the medicinal products for which marketing authorisations have been refused, revoked or suspended, whose supply has been prohibited or which have been withdrawn from the market.’.

27.In Article 126a, paragraphs 2 and 3 are replaced by the following: ‘2. When a Member State avails itself of this possibility, it shall adopt the necessary measures in order to ensure that the requirements of this Directive are complied with, in particular those referred to in Titles V, VI, VIII, IX and XI. Member States may decide that Article 63(1) and (2) shall not apply to medicinal products authorised under paragraph 1.

Before granting such a marketing authorisation, a Member State:

(a)shall notify the marketing authorisation holder, in the Member State in which the medicinal product concerned is authorised, of the proposal to grant a marketing authorisation under this Article in respect of the medicinal product concerned. (b)may request the competent authority in that Member State to submit copies of the assessment report referred to in Article 21(4) and of the marketing authorisation in force in respect of the medicinal product concerned. If so requested, the competent authority in that Member State shall supply, within 30 days of receipt of the request, a copy of the assessment report and the marketing authorisation in respect of the medicinal product concerned.’.

28.Article 127a is replaced by the following: ‘Article 127a When a medicinal product is to be authorised in accordance with Regulation (EC) No 726/2004, and the Committee for Medicinal Products for Human Use in its opinion refers to recommended conditions or restrictions as provided for in points (c), (ca), (cb) or (cc) of Article 9(4) thereof, the Commission may adopt a decision addressed to the Member States, in accordance with Articles 33 and 34 of this Directive, for the implementation of those conditions or restrictions.’.

Article 2

Transitional provisions

With regard to the obligation on the part of the marketing authorisation holder to maintain and make available on request a pharmacovigilance system master file in respect of one or more medicinal products provided for in Article 104(3)(b) of Directive 2001/83/EC as amended by this Directive, the Member States shall ensure that that obligation applies to marketing authorisations granted before 21 July 2012 as from either:

a)the date on which those marketing authorisations are renewed; or

b)21 July 2015

whichever is earlier.

The Member States shall ensure that the procedure provided for in Articles 107m to 107q of Directive 2001/83/EC as amended by this Directive applies only to studies which have commenced after 21 July 2012.

With regard to the obligation on the part of the marketing authorisation holder to submit information on suspected adverse reactions electronically to the Eudravigilance database, provided for in Article 107(3) of Directive 2001/83/EC as amended by this Directive, the Member States shall ensure that this obligation applies as from 6 months after the functionalities of the database are established and have been announced by the Agency.

Until the Agency can ensure the functionalities of the Eudravigilance database as specified in Article 24 of Regulation (EC) No 726/2004 as amended by Regulation (EU) No 1235/2010 ([^E0014]) of the European Parliament and of the Council, marketing authorisation holders shall report, within 15 days of the day on which the holder concerned gained knowledge of the event, all serious suspected adverse reactions that occur in the Union, to the competent authority of the Member State on whose territory the incident occurred and shall report all serious suspected adverse reactions that occur on the territory of a third country to the Agency and, if requested, to the competent authorities of the Member States in which the medicinal product is authorised.

Until the Agency can ensure the functionalities of the Eudravigilance database as specified in Article 24 of Regulation (EC) No 726/2004 as amended by Regulation (EU) No 1235/2010, the competent authority of a Member State may require marketing authorisation holders to report to it all non-serious suspected adverse reactions that occur on the territory of that Member State, within 90 days of the day on which the marketing authorisation holder concerned gained knowledge of the event.

During this period, Member States shall ensure that the reports referred to in paragraph 4 that relate to events that occurred in their territory are promptly made available to the Eudravigilance database, and in any case within 15 days of the notification of suspected serious adverse reactions.

With regard to the obligation on the part of the marketing authorisation holder to submit periodic safety update reports to the Agency as provided for in Article 107b(1) of Directive 2001/83/EC as amended by this Directive, the national competent authorities shall ensure that this obligation applies as from 12 months after the functionalities of the repository have been established and have been announced by the Agency.

Until the Agency can ensure the functionalities agreed for the repository of the periodic safety update reports, the marketing authorisation holders shall submit the periodic safety reports to all Member States in which the medicinal product has been authorised.

Article 3

Transposition

Member States shall adopt and publish, by 21 July 2012 at the latest, the laws, regulations and administrative provisions necessary to comply with this Directive. They shall forthwith communicate to the Commission the text of those provisions.

They shall apply those provisions from 21 July 2012.

When Member States adopt those provisions, they shall contain a reference to this Directive or be accompanied by such a reference on the occasion of their official publication. Member States shall determine how such reference is to be made.

Member States shall communicate to the Commission the text of the main provisions of national law which they adopt in the field covered by this Directive.

Article 4

Entry into force

This Directive shall enter into force on the 20th day following its publication in the Official Journal of the European Union.

Article 5

Addressees

This Directive is addressed to the Member States.

[^E0001]: OJ C 306, 16.12.2009, p. 28.

[^E0002]: OJ C 79, 27.3.2010, p. 50.

[^E0003]: OJ C 229, 23.9.2009, p. 19.

[^E0004]: Position of the European Parliament of 22 September 2010 [not yet published in the Official Journal] and Council Decision of 29 November 2010.

[^E0005]: OJ L 311, 28.11.2001, p. 67.

[^E0006]: OJ L 136, 30.4.2004, p. 1.

[^E0007]: OJ L 121, 1.5.2001, p. 34.

[^E0008]: OJ L 281, 23.11.1995, p. 31.

[^E0009]: OJ L 8, 12.1.2001, p. 1.

[^E0010]: OJ L 218, 13.8.2008, p. 30.

[^E0011]: OJ L 184, 17.7.1999, p. 23.

[^E0012]: OJ C 321, 31.12.2003, p. 1.

[^E0013]: OJ L 262, 14.10.2003, p. 22.’.

[^E0014]: See page 1 of this Official Journal.

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