TITLE IX

PHARMACOVIGILANCE
CHAPTER 1

General provisions
Article 101
1
Member States shall operate a pharmacovigilance system for the fulfilment of their pharmacovigilance tasks and their participation in Union pharmacovigilance activities.
The pharmacovigilance system shall be used to collect information on the risks of medicinal products as regards patients’ or public health. That information shall in particular refer to adverse reactions in human beings, arising from use of the medicinal product within the terms of the marketing authorisation as well as from use outside the terms of the marketing authorisation, and to adverse reactions associated with occupational exposure.
2
Member States shall, by means of the pharmacovigilance system referred to in paragraph 1, evaluate all information scientifically, consider options for risk minimisation and prevention and take regulatory action concerning the marketing authorisation as necessary. They shall perform a regular audit of their pharmacovigilance system and report the results to the Commission on
21 September 2013
at the latest and then every 2 years thereafter.
3
Each Member State shall designate a competent authority for the performance of pharmacovigilance tasks.
4
The Commission may request Member States to participate, under the coordination of the Agency, in international harmonisation and standardisation of technical measures in relation to pharmacovigilance.
Article 102
The Member States shall:
1. take all appropriate measures to encourage patients, doctors, pharmacists and other healthcare professionals to report suspected adverse reactions to the national competent authority; for these tasks, organisations representing consumers, patients and healthcare professionals may be involved as appropriate;
2. facilitate patient reporting through the provision of alternative reporting formats in addition to web-based formats;
3. take all appropriate measures to obtain accurate and verifiable data for the scientific evaluation of suspected adverse reaction reports;
4. ensure that the public is given important information on pharmacovigilance concerns relating to the use of a medicinal product in a timely manner through publication on the web-portal and through other means of publicly available information as necessary;
5. ensure, through the methods for collecting information and where necessary through the follow-up of suspected adverse reaction reports, that all appropriate measures are taken to identify clearly any biological medicinal product prescribed, dispensed, or sold in their territory which is the subject of a suspected adverse reaction report, with due regard to the name of the medicinal product, in accordance with Article 1(20), and the batch number;
6. take the necessary measures to ensure that a marketing authorisation holder who fails to discharge the obligations laid down in this Title is subject to effective, proportionate and dissuasive penalties.
For the purposes of point (a) and (e) of the first paragraph the Member States may impose specific obligations on doctors, pharmacists and other health-care professionals.
Article 103
A Member State may delegate any of the tasks entrusted to it under this Title to another Member State subject to a written agreement of the latter. Each Member State may represent no more than one other Member State.
The delegating Member State shall inform the Commission, the Agency and all other Member States of the delegation in writing. The delegating Member State and the Agency shall make that information public.
Article 104
1
The marketing authorisation holder shall operate a pharmacovigilance system for the fulfilment of his pharmacovigilance tasks equivalent to the relevant Member State’s pharmacovigilance system provided for under Article 101(1).
2
The marketing authorisation holder shall by means of the pharmacovigilance system referred to in paragraph 1 evaluate all information scientifically, consider options for risk minimisation and prevention and take appropriate measures as necessary.
The marketing authorisation holder shall perform a regular audit of his pharmacovigilance system. He shall place a note concerning the main findings of the audit on the pharmacovigilance system master file and, based on the audit findings, ensure that an appropriate corrective action plan is prepared and implemented. Once the corrective actions have been fully implemented, the note may be removed.
3
As part of the pharmacovigilance system, the marketing authorisation holder shall:
a
have permanently and continuously at his disposal an appropriately qualified person responsible for pharmacovigilance;
b
maintain and make available on request a pharmacovigilance system master file;
c
operate a risk management system for each medicinal product;
d
monitor the outcome of risk minimisation measures which are contained in the risk management plan or which are laid down as conditions of the marketing authorisation pursuant to Articles 21a, 22 or 22a;
e
update the risk management system and monitor pharmacovigilance data to determine whether there are new risks or whether risks have changed or whether there are changes to the benefit-risk balance of medicinal products.
The qualified person referred to in point (a) of the first subparagraph shall reside and operate in the Union and shall be responsible for the establishment and maintenance of the pharmacovigilance system. The marketing authorisation holder shall submit the name and contact details of the qualified person to the competent authority and the Agency.
4
Notwithstanding the provisions of paragraph 3, national competent authorities may request the nomination of a contact person for pharmacovigilance issues at national level reporting to the qualified person responsible for pharmacovigilance activities.
Article 104a
1
Without prejudice to paragraphs 2, 3 and 4 of this Article, holders of marketing authorisations granted before
21 July 2012
shall, by way of derogation from Article 104(3)(c), not be required to operate a risk management system for each medicinal product.
2
The national competent authority may impose an obligation on a marketing authorisation holder to operate a risk management system, as referred to in Article 104(3)(c), if there are concerns about the risks affecting the risk-benefit balance of an authorised medicinal product. In that context, the national competent authority shall also oblige the marketing authorisation holder to submit a detailed description of the risk-management system which he intends to introduce for the medicinal product concerned.
The imposition of such obligations shall be duly justified, notified in writing and shall include the timeframe for submission of the detailed description of the risk-management system.
3
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.
4
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 accordingly to include the measures to be taken as part of the risk management system as conditions of the marketing authorisation referred to in point (a) of Article 21a.
Article 105
The management of funds intended for activities connected with pharmacovigilance, the operation of communication networks and market surveillance shall be under the permanent control of the national competent authorities in order to guarantee their independence in the performance of those pharmacovigilance activities.
The first paragraph shall not preclude the national competent authorities from charging fees to marketing authorisation holders for performing those activities by the national competent authorities on the condition that their independence in the performance of those pharmacovigilance activities is strictly guaranteed.
CHAPTER 2

Transparency and communications
Article 106
Each Member State shall set up and maintain a national medicines web-portal which shall be linked to the European medicines web-portal established in accordance with Article 26 of Regulation (EC) No 726/2004. By means of the national medicines web-portals, the Member States shall make publicly available at least the following:
1. public assessment reports, together with a summary thereof;
2. summaries of product characteristics and package leaflets;
3. summaries of risk management plans for medicinal products authorised in accordance with this Directive;
4. the list of medicinal products referred to in Article 23 of Regulation (EC) No 726/2004;
5. information on the different ways of reporting suspected adverse reactions to medicinal products to national competent authorities by healthcare professionals and patients, including the web-based structured forms referred to in Article 25 of Regulation (EC) No 726/2004.
Article 106a
1
As soon as the marketing authorisation holder intends to make a public announcement relating to information on pharmacovigilance concerns in relation to the use of a medicinal product, and in any event at the same time or before the public announcement is made, he shall be required to inform the national competent authorities, the Agency and the Commission.
The marketing authorisation holder shall ensure that information to the public is presented objectively and is not misleading.
2
Unless urgent public announcements are required for the protection of public health, the Member States, the Agency and the Commission shall inform each other not less than 24 hours prior to a public announcement relating to information on pharmacovigilance concerns.
3
For active substances contained in medicinal products authorised in more than one Member State, the Agency shall be responsible for the coordination between national competent authorities of safety announcements and shall provide timetables for the information being made public.
Under the coordination of the Agency, the Member States shall make all reasonable efforts to agree on a common message in relation to the safety of the medicinal product concerned and the timetables for their distribution. The Pharmacovigilance Risk Assessment Committee shall, at the request of the Agency, provide advice on those safety announcements.
4
When the Agency or national competent authorities make public information referred to in paragraphs 2 and 3, any information of a personal or commercially confidential nature shall be deleted unless its public disclosure is necessary for the protection of public health.
CHAPTER 3

Recording, reporting and assessment of pharmacovigilance data
Section 1

Recording and reporting of suspected adverse reactions
Article 107
1
Marketing authorisation holders shall record all suspected adverse reactions in the Union or in third countries which are brought to their attention, whether reported spontaneously by patients or healthcare professionals, or occurring in the context of a post-authorisation study.
Marketing authorisation holders shall ensure that those reports are accessible at a single point within the Union.
By way of derogation from the first subparagraph, suspected adverse reactions occurring in the context of a clinical trial shall be recorded and reported in accordance with Directive 2001/20/EC.
2
Marketing authorisation holders shall not refuse to consider reports of suspected adverse reactions received electronically or by any other appropriate means from patients and healthcare professionals.
3
Marketing authorisation holders shall submit electronically to the database and data-processing network referred to in Article 24 of Regulation (EC) No 726/2004 (hereinafter referred to as the
‘
Eudravigilance database
’
) information on all serious suspected adverse reactions that occur in the Union and in third countries within 15 days following the day on which the marketing authorisation holder concerned gained knowledge of the event.
Marketing authorisation holders shall submit electronically to the Eudravigilance database information on all non-serious suspected adverse reactions that occur in the Union, within 90 days following the day on which the marketing authorisation holder concerned gained knowledge of the event.
For medicinal products containing the active substances referred to in the list of publications monitored by the Agency pursuant to Article 27 of Regulation (EC) No 726/2004, marketing authorisation holders shall not be required to report to the Eudravigilance database the suspected adverse reactions recorded in the listed medical literature, but they shall monitor all other medical literature and report any suspected adverse reactions.
4
Marketing authorisation holders shall establish procedures in order to obtain accurate and verifiable data for the scientific evaluation of suspected adverse reaction reports. They shall also collect follow-up information on these reports and submit the updates to the Eudravigilance database.
5
Marketing authorisation holders shall collaborate with the Agency and the Member States in the detection of duplicates of suspected adverse reaction reports.
Article 107a
1
Each Member State shall record all suspected adverse reactions that occur in its territory which are brought to its attention from healthcare professionals and patients. Member States shall involve patients and healthcare professionals, as appropriate, in the follow-up of any reports they receive in order to comply with Article 102(c) and (e).
Member States shall ensure that reports of such reactions may be submitted by means of the national medicines web-portals or by other means.
2
For reports submitted by a marketing authorisation holder, Member States on whose territory the suspected adverse reaction occurred may involve the marketing authorisation holder in the follow-up of the reports.
3
Member States shall collaborate with the Agency and the marketing authorisation holders in the detection of duplicates of suspected adverse reaction reports.
4
Member States shall, within 15 days following the receipt of the reports of serious suspected adverse reactions referred to in paragraph 1, submit the reports electronically to the Eudravigilance database.
They shall, within 90 days from the receipt of reports referred to in paragraph 1, submit reports of non-serious suspected adverse reactions electronically to the Eudravigilance database.
Marketing authorisation holders shall access those reports through the Eudravigilance database.
5
Member States shall ensure that reports of suspected adverse reactions arising from an error associated with the use of a medicinal product that are brought to their attention are made available to the Eudravigilance database and to any authorities, bodies, organisations and/or institutions, responsible for patient safety within that Member State. They shall also ensure that the authorities responsible for medicinal products within that Member State are informed of any suspected adverse reactions brought to the attention of any other authority within that Member State. These reports shall be appropriately identified in the forms referred to in Article 25 of Regulation (EC) No 726/2004.
6
Unless there are justifiable grounds resulting from pharmacovigilance activities, individual Member States shall not impose any additional obligations on marketing authorisation holders for the reporting of suspected adverse reactions.
Section 2

Periodic safety update reports
Article 107b
1
Marketing authorisation holders shall submit to the Agency periodic safety update reports containing:
a
summaries of data relevant to the benefits and risks of the medicinal product, including results of all studies with a consideration of their potential impact on the marketing authorisation;
b
a scientific evaluation of the risk-benefit balance of the medicinal product;
c
all data relating to the volume of sales of the medicinal product and any data in possession of the marketing authorisation holder relating to the volume of prescriptions, including an estimate of the population exposed to the medicinal product.
The evaluation referred to in point (b) shall be based on all available data, including data from clinical trials in unauthorised indications and populations.
The periodic safety update reports shall be submitted electronically.
2
The Agency shall make available the reports referred to in paragraph 1 to the national competent authorities, the members of the Pharmacovigilance Risk Assessment Committee, the Committee for Medicinal Products for Human Use and the coordination group by means of the repository referred to in Article 25a of Regulation (EC) No 726/2004.
3
By way of derogation from paragraph 1 of this Article, the holders of marketing authorisations for medicinal products referred to in Article 10(1), or Article 10a, and the holders of registrations for medicinal products referred to in Articles 14 or 16a, shall submit periodic safety update reports for such medicinal products in the following cases:
a
where such obligation has been laid down as a condition in the marketing authorisation in accordance with Article 21a or Article 22; or
b
when requested by a competent authority on the basis of concerns relating to pharmacovigilance data or due to the lack of periodic safety update reports relating to an active substance after the marketing authorisation has been granted. The assessment reports of the requested periodic safety update reports shall be communicated to the Pharmacovigilance Risk Assessment Committee, which shall consider whether there is a need for a single assessment report for all marketing authorisations for medicinal products containing the same active substance and inform the coordination group or the Committee for Medicinal Products for Human Use accordingly, in order to apply the procedures laid down in Article 107c(4) and Article 107e.
Article 107c
1
The frequency with which the periodic safety update reports are to be submitted shall be specified in the marketing authorisation.
The dates of submission according to the specified frequency shall be calculated from the date of the authorisation.
2
Holders of marketing authorisations which were granted before
21 July 2012
, and for which the frequency and dates of submission of the periodic safety update reports are not laid down as a condition to the marketing authorisation, shall submit the periodic safety update reports in accordance with the second subparagraph of this paragraph until another frequency or other dates of submission of the reports are laid down in the marketing authorisation or determined in accordance with paragraphs 4, 5 or 6.
Periodic safety update reports shall be submitted to the competent authorities immediately upon request or in accordance with the following:
a
where a medicinal product has not yet been placed on the market, at least every 6 months following authorisation and until the placing on the market;
b
where a medicinal product has been placed on the market, at least every 6 months during the first 2 years following the initial placing on the market, once a year for the following 2 years and at three-yearly intervals thereafter.
3
Paragraph 2 shall also apply to medicinal products which are authorised only in one Member State and for which paragraph 4 does not apply.
4
Where medicinal products that are subject to different marketing authorisations contain the same active substance or the same combination of active substances, the frequency and dates of submission of the periodic safety update reports resulting from the application of paragraphs 1 and 2 may be amended and harmonised to enable a single assessment to be made in the context of a periodic safety update report work-sharing procedure and to set a Union reference date from which the submission dates are calculated.
This harmonised frequency for the submission of the reports and the Union reference date may be determined, after consultation of the Pharmacovigilance Risk Assessment Committee, by one of the following:
a
the Committee for Medicinal Products for Human Use, where at least one of the marketing authorisations for the medicinal products containing the active substance concerned has been granted in accordance with the centralised procedure provided for in Chapter 1 of Title II of Regulation (EC) No 726/2004;
b
the coordination group, in other cases than those referred to in point (a).
The harmonised frequency for the submission of the reports determined pursuant to the first and second subparagraphs shall be made public by the Agency. Marketing authorisation holders shall submit an application for a variation of the marketing authorisation accordingly.
5
For the purposes of paragraph 4, the Union reference date for medicinal products containing the same active substance or the same combination of active substances shall be one of the following:
a
the date of the first marketing authorisation in the Union of a medicinal product containing that active substance or that combination active substances;
b
if the date referred to in point (a) cannot be ascertained, the earliest of the known dates of the marketing authorisations for a medicinal product containing that active substance or that combination of active substances.
6
Marketing authorisation holders shall be allowed to submit requests to the Committee for Medicinal Products for Human Use or the coordination group, as appropriate, to determine Union reference dates or to change the frequency of submission periodic safety update reports on one of the following grounds:
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.
7
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
1
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).
2
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.
3
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
1
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.
2
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 maintain, vary, suspend or revoke the marketing authorisations concerned in accordance with the timetable for implementation determined in the agreement.
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.
3
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.
4
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
1
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.
2
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.
3
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
1
A Member State or the Commission, as appropriate, shall, on the basis of concerns resulting from the evaluation of data from pharmacovigilance activities, initiate the procedure provided for in this section by informing the other Member States, the Agency and the Commission where:
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; or
d
it is informed by the marketing authorisation holder that, on the basis of safety concerns, the holder has interrupted the placing on the market of a medicinal product or has taken action to have a marketing authorisation withdrawn, or intends to take such action or has not applied for the renewal of a marketing authorisation.
1a
A Member State or the Commission, as appropriate, shall, on the basis of concerns resulting from the evaluation of data from pharmacovigilance activities, inform the other Member States, the Agency and the Commission where it considers that a new contraindication, a reduction in the recommended dose or a restriction to the indications of a medicinal product is necessary. The information shall outline the action considered and the reasons therefor.
Any Member State or the Commission, as appropriate, shall, when urgent action is considered necessary, initiate the procedure provided for in this section in any of the cases referred to in this paragraph.
Where the procedure provided for in this section is not initiated, for medicinal products authorised in accordance with the procedures laid down in Chapter 4 of Title III, the case shall be brought to the attention of the coordination group.
Article 31 shall be applicable where the interests of the Union are involved.
1b
Where the procedure provided for in this section is initiated, 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 the information that the procedure has been initiated available to marketing authorisation holders.
2
Without prejudice to the provisions of
paragraphs 1 and 1a 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.
3
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 paragraphs 1 and 1a
, 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.
4
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.
5
At the time of the information referred to
in paragraphs 1 and 1a,
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
1
Following receipt of the information referred to
in paragraphs 1 and 1a of Article 107i,
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.
2
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.
3
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
1
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.
2
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 maintain, vary, suspend, revoke or refuse renewal of 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.
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.
3
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.
4
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
1
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.
2
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.
3
The studies shall not be performed where the act of conducting the study promotes the use of a medicinal product.
4
Payments to healthcare professionals for participating in non-interventional post-authorisation safety studies shall be restricted to the compensation for time and expenses incurred.
5
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.
6
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.
7
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.
8
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
1
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.
2
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:
1. it considers that the conduct of the study promotes the use of a medicinal product;
2. 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.
3
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
1
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.
2
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.
3
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
1
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.
2
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:
1. the content and maintenance of the pharmacovigilance system master file kept by the marketing authorisation holder;
2. the minimum requirements for the quality system for the performance of pharmacovigilance activities by the national competent authorities and the marketing authorisation holder;
3. the use of internationally agreed terminology, formats and standards for the performance of pharmacovigilance activities;
4. the minimum requirements for the monitoring of data in the Eudravigilance database to determine whether there are new risks or whether risks have changed;
5. the format and content of the electronic transmission of suspected adverse reactions by Member States and the marketing authorisation holder;
6. the format and content of electronic periodic safety update reports and risk management plans;
7. 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:
1. guidance on good pharmacovigilance practices for both competent authorities and marketing authorisation holders;
2. 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.
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).
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).