Pharmacovigilance Regulations, 2012

L.N. 369 of 2012

MEDICINES ACT

(CAP. 458)

Pharmacovigilance Regulations, 2012

IN exercise of the powers conferred by article 106 of the

Medicines Act, the Minister of Health, the Elderly and Community

Care, after consultation with the Licensing Authority, has made the

following regulations:-

(1) The title of these

regulations

is

the Citation,

purpose and

Pharmacovigilance Regulations, 2012.

scope.

(2) These regulations implement the provisions of 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.

(3) These regulations shall apply to authorised medicinal

products for human use and any pharmacovigilance activity

connected therewith.

For the purpose of these regulations

Interpretation.

"the Act" means the Medicines Act;

"adverse reaction" means a response to a medicinal product

which is noxious and unintended;

"the Agency" means the European Medicines Agency

established by Regulation (EC) No 2004/726;

"the Authority" means the Medicines Authority established

under article 4 of the Act;

"the Commission" means the Commission in accordance with

Council Decision 1999/468/EC of the 28th June, 1999;

"the Community" means the European Union and the European

Economic Area;

"Member State" means a State which is a member of the

Community;

"serious adverse reaction" means an adverse reaction which

results in death, or is life threatening, or requires in-patient

hospitalisation or the prolongation of existing hospitalisation, or

which results in persistent or significant disability or incapacity, or is

a congenital anomaly or birth defect;

"periodic safety update reports" means the periodical reports

containing the records referred to in regulation 31;

"pharmacovigilance system" means a system used by the

marketing authorisation holder and by Member States to fulfil the

tasks and responsibilities listed in these regulations and designed to

monitor the safety of authorised medicinal products and detect any

change to their risk-benefit balance;

"pharmacovigilance system master file" means a detailed

description of the pharmacovigilance system used by the marketing

authorisation holder with respect to one or more authorised medicinal

products;

"post-authorisation safety study" means any study relating to an

authorised medicinal product conducted with the aim of identifying,

characterising or quantifying a safety hazard, confirming the safety

profile of the medicinal product, or of measuring the effectiveness of

risk management measures;

"risk-benefit balance" means an evaluation of the positive

therapeutic effects of the medicinal product in relation to any risk

relating to the quality, safety or efficacy of the medicinal product as

regards patients’ health or public health;

"risk management system" means a set of pharmacovigilance

activities and interventions designed to identify, characterise, prevent

or minimise risks relating to a medicinal product, including the

assessment of the effectiveness of those activities and interventions;

"risk management plan” means a detailed description of the risk

management system;

"unexpected adverse reaction" means an adverse reaction, the

nature, severity or outcome of which is not consistent with the

summary of product characteristics.

(1) The Authority shall set up and operate a

pharmacovigilance system for the fulfilment of its pharmacovigilance

tasks and its participation in Community 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) By means of the pharmacovigilance system referred to in

sub-regulation (1), the Authority shall evaluate all information

scientifically, consider options for risk minimisation and prevention

and take regulatory action concerning the marketing authorisation as

necessary. A regular audit of its pharmacovigilance system shall be

carried out and the results reported to the Commission on the 21st

September, 2013 at the latest and then every two years thereafter.

(3) The suitable information collected within this system shall

be communicated by the Authority to the other Member States and

the Agency. The information shall be recorded in the database

referred to in point (l) of the second subparagraph of Article 57(1) of

Regulation (EC) No 726/2004 and shall be permanently accessible to

all Member States and without delay to the public.

(4) It shall be the duty of doctors and other healthcare

professionals to immediately report to the Authority any suspected

adverse reaction to a medicinal product in Malta.

(5) The Authority shall facilitate patient reporting through the

provision of alternative reporting formats in addition to web-based

formats as well as take all appropriate measures to obtain accurate

and verifiable data for the scientific evaluation of suspected adverse

reaction reports. The Authority shall also 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.

(6) The Authority shall 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, and the batch number.

(7) The Authority shall also take the necessary measures to

ensure that a marketing authorisation holder who fails to discharge

the obligations laid down in these regulations is subject to effective,

proportionate and dissuasive penalties.

The Authority may delegate any of the tasks entrusted to it Power to

delegate.

under these regulations to another Member State subject to a written

agreement of the latter.

The Authority 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.

(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 regulation 3.

(2) The marketing authorisation holder shall, by means of the

pharmacovigilance system referred to in sub-regulation (1), evaluate

all information scientifically, consider options for risk minimisation

and prevention and take appropriate measures as necessary.

(3) 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.

(4) 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;

(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

Provided that the qualified person referred to in paragraph (a)

shall reside and operate in the European 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

Authority and the Agency.

(5) Notwithstanding the provisions of sub-regulation (3), the

Authority may request the nomination of a contact person for

pharmacovigilance issues at national level reporting to the qualified

person responsible for pharmacovigilance activities.

Without prejudice to regulation 6(2), (3) and (4), holders of Derogation.

marketing authorisations granted before the 21st July, 2012 shall, by

way of derogation from regulation 6(4)(c), not be required to operate

a risk management system for each medicinal product.

The Authority may impose an obligation on a marketing The Authority

authorisation holder to operate a risk management system, as referred may

obligation.

to in regulation 6(4)(c), if there are concerns about the risks affecting

the risk-benefit balance of an authorised medicinal product. In that

context, the 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.

The Authority shall provide the marketing authorisation Opportunity to

holder with an opportunity to present written observations in response file

observations.

to the imposition of the obligation within a time limit which it shall

specify, if the marketing authorisation holder so requests within thirty

days of receipt of the written notification of the obligation.

On the basis of the written observations submitted by the Authority may

marketing authorisation holder, the Authority shall withdraw or withdraw

confirm

confirm the obligation. Where the Authority confirms the obligation, 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.

The management of funds intended for activities connected Management of

with pharmacovigilance, the operation of communication networks funds

for activities

and market surveillance shall be under the permanent control of the connected

pharmacovigila

Authority in order to guarantee their independence in the performance nce.

of those pharmacovigilance activities.

Regulation 11 shall not preclude the Authority from

charging fees to marketing authorisation holders for performing those

activities by the Authority on the condition that its independence in

the performance of those pharmacovigilance activities is strictly

guaranteed.

The Authority 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 Authority shall make publicly available the

following

(a)

public assessment reports, together with a summary

thereof;

(b)

summaries of product characteristics and package

leaflets;

(c)

summaries of risk management plans for medicinal

products authorised in accordance with Directive 2001/83/EC as

amended;

(d) the list of medicinal products referred to in Article

23 of Regulation (EC) No 726/2004;

(e)

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.

(1) A marketing authorisation holder shall inform the

Authority, the Agency and the Commission if it intends to make a

public announcement relating to information on pharmacovigilance

concerns in relation to the use of a medicinal product. The marketing

authorisation holder shall inform the authorities at the same time or

before the public announcement is made. 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 Authority, the Agency and the

Commission shall inform each other not less than twenty-four hours

prior to the making of 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 Authority 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.

(4) When the Agency or the Authority make public

information referred to in sub-regulations (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.

Marketing authorisation holders shall record all suspected Recording,

adverse reactions in the Community or in third countries which are reporting

assessment of

brought to their attention, whether reported spontaneously by patients pharmacovigila

nce data.

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 Community

Provided that that by way of derogation from the above,

suspected adverse reactions occurring in the context of a clinical trial

shall be recorded and reported in accordance with Directive 2001/20/

EC.

Marketing authorisation holders shall not refuse to Electronic

consider reports of suspected adverse reactions received reports

adverse

electronically or by any other appropriate means from patients and reactions.

healthcare professionals.

Marketing authorisation holders shall submit electronically Eudravigilance

to the database and data-processing network referred to in Article 24 database.

of Regulation (EC) No 726/2004, hereinafter referred to as the

"Eudravigilance database", information on all serious suspected

adverse reactions that occur in the European Union and in third

countries within fifteen days following the day on which the

marketing authorisation holder concerned gained knowledge of the

event.

(1) Marketing authorisation holders shall submit Non-serious

electronically to the Eudravigilance database information on all non- suspected

adverse

serious suspected adverse reactions that occur in the European Union, reactions.

within ninety days following the day on which the marketing

authorisation holder concerned gained knowledge of the event.

(2) 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.

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.

Marketing authorisation holders shall collaborate with the

Agency and the Member States in the detection of duplicates of

suspected adverse reaction reports.

The Authority shall record all suspected adverse reactions

that occur in its territory which are brought to its attention from

healthcare professionals and patients. The Authority shall involve

patients and healthcare professionals, as appropriate, in the follow-up

of any reports they receive in order to comply with the provisions of

regulation 3(5) and (6).

The Authority shall ensure that reports of such reactions

may be submitted by means of the national medicines web-portals or

by other means.

For reports submitted by a marketing authorisation holder,

where the suspected adverse reaction occurred in Malta, the Authority

may involve the marketing authorisation holder in the follow-up of

the reports.

The Authority shall collaborate with the Agency and the

marketing authorisation holders in the detection of duplicates of

suspected adverse reaction reports.

(1) The Authority shall, within fifteen days following

the receipt of the reports of serious suspected adverse reactions

referred to in regulation 21, submit the reports electronically to the

Eudravigilance database.

(2) The Authority shall, within ninety days from the receipt of

reports referred to in regulation 21, submit reports of non-serious

suspected adverse reactions electronically to the Eudravigilance

database.

Marketing authorisation holders shall access such reports

as are referred to in regulation 25 through the Eudravigilance

database.

The Authority shall ensure that reports of suspected Reactions

adverse reactions arising from an error associated with the use of a arising

error.

medicinal product that are brought to its attention are made available

to the Eudravigilance database.

Unless there are justifiable grounds resulting from Additional

pharmacovigilance activities, the Authority shall not impose any obligations

not be imposed.

additional obligations on marketing authorisation holders for the

reporting of suspected adverse reactions.

(1) Marketing authorisation holders shall submit to the Periodic safety

update reports.

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.

(2) The evaluation referred to in sub-regulation (1)(b) shall be

based on all available data, including data from clinical trials in

unauthorised indications and populations.

(3) The periodic safety update reports shall be submitted

electronically.

The Agency shall make available the reports referred to in Agency to make

regulation 29 to the Authority, the members of the Pharmacovigilance reports

available.

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.

(1) By way of derogation from regulation 29, the When reports

holders of marketing authorisations for medicinal products referred to are

submitted.

in Directive 2001/83/EC, Article 10(1), or Directive 2001/83/EC,

Article 10a, and the holders of registrations for medicinal products

referred to in Directive 2001/83/EC, Article 14, or Directive 2001/83/

EC, Article 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; 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.

(2) The assessment reports of the requested periodic safety

update reports shall be communicated to the Agency’s

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 of

Directive 2001/83/EC.

(1) The frequency with which the periodic safety update

reports are to be submitted shall be specified in the marketing

authorisation.

(2) The dates of submission according to the specified

frequency shall be calculated from the date of the authorisation.

(1) Holders of marketing authorisations which were

granted before the 21st July, 2012, and for which the frequency and

2012. 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 sub-regulation (2)

until another frequency or other dates of submission of the reports are

laid down in the marketing authorisation or determined in accordance

with regulations 35, 36 or 37.

(2) Periodic safety update reports shall be submitted to the

Authority 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 six months following authorisation

and until the placing on the market;

(b) where a medicinal product has been placed on the

market, at least every six months during the first two years

following the initial placing on the market, once a year for the

following two years and at three-yearly intervals thereafter.

Regulation 33 shall also apply to medicinal products which Medicinal

are authorised only in one Member State and for which regulation 35 products

authorised only

in one Member

does not apply.

State.

(1) Where medicinal products that are subject to Harmonised

different marketing authorisations contain the same active substance frequency

submission of

or the same combination of active substances, the frequency and dates reports.

of submission of the periodic safety update reports resulting from the

application of regulations 32 and 33 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 Community

reference date from which the submission dates are calculated.

(2) This harmonised frequency for the submission of the

reports and the Community reference date may be determined, after

consultation of the Agency’s 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 paragraph (a).

(3) The harmonised frequency for the submission of the

reports determined pursuant to the sub-regulations (1) and (2) shall be

made public by the Agency. Marketing authorisation holders shall

submit an application for a variation of the marketing authorisation

accordingly.

For the purposes of regulation 35, the Community Community

reference date for medicinal products containing the same active reference date.

substance or the same combination of active substances shall be one

of the following

(a)

the date of the first marketing authorisation in the

Community of a medicinal product containing that active

substance or that combination active substances;

(b) if the date referred to in paragraph (a) cannot be

ascertained, the earliest of the known dates of the marketing

authorisations for medicinal products containing that active

substance or that combination of active substances.

(1) Marketing authorisation holders shall be allowed to

submit requests to the Agency’s Committee for Medicinal Products

for Human Use or the coordination group, as appropriate, to

determine the Community reference dates or to change the frequency

of submission of 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.

(2) 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

Agency’s Pharmacovigilance Risk Assessment Committee, 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 Community

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 regulations 35, 36 and 37 shall take

effect six months after the date of such publication.

The Authority shall, when it is a reference member state or

a rapporteur at the Agency’s Pharmacovigilance Risk Assessment

committee, 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.

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 of

Directive 2001/83/EC, for all medicinal products containing the same

active substance or the same combination of active substances and for

which a Community 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.

The Member State or rapporteur, as appropriate, shall Assessment

prepare an assessment report within sixty days of receipt of the report.

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 thirty days of receipt of the assessment report, the Submission of

Member States and the marketing authorisation holder may submit comments.

comments to the Agency and to the rapporteur or Member State.

Following the receipt of the comments referred to in Rapporteur to

regulation 44, the rapporteur or Member State shall within fifteen update

assessment

days update the assessment report taking into account any comments report.

submitted, and forward it to the Agency’s Pharmacovigilance Risk

Assessment Committee. The Agency’s 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.

Following the assessment of periodic safety update reports, Authority to

the Authority shall consider whether any action concerning the consider

necessity of any

marketing authorisation for the medicinal product concerned is action.

necessary. The Licensing Authority as established under article 3 of

the Act, shall maintain, vary, suspend or revoke the marketing

authorisation as appropriate.

In the case of a single assessment of periodic safety update Coordination

reports that recommends any action concerning more than one group

consider the

marketing authorisation in accordance with Article 107e(1) of report.

Directive 2001/83/EC as amended, 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.

(1) 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.

(2) 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.

(3) 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 of Directive

2001/83/EC as amended.

(4) 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) of

Directive 2001/83/EC as amended 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 thirty 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 Agency’s Committee for Detailed

Medicinal Products for Human Use differs from the recommendation explanation

scientific

of the Pharmacovigilance Risk Assessment Committee, the grounds.

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.

(1) On the basis of the opinion of the Agency’s Decisions to be

Committee for Medicinal Products for Human Use referred to in adopted

Commission.

regulation 50, 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 herein; 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 herein.

(2) Articles 33 and 34 of Directive 2001/83/EC as amended

shall apply to the adoption of the decision referred to in sub-

regulation (1)(a) and to its implementation by the Member States.

Article 10 of Regulation (EC) No 726/2004 shall apply to Decision on

the decision referred to in regulation 51(1)(b). Where the measures

relating to

Commission adopts such decision, it may also adopt a decision marketing

authorisations.

addressed to the Member States pursuant to Article 127a of Directive

2001/83/EC as amended.

Regarding medicinal products authorised in accordance Signal

with Directive 2001/83/EC as amended, the Authority in detection.

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 of Directive 2001/83/EC as

amended;

(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.

The Authority 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.

(1) The Authority or the Commission, as appropriate,

shall initiate the procedure provided for herein, 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

Provided that 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.

(2) 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

of Directive 2001/83/EC as amended 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.

(3) (a)

Without prejudice to the provisions of sub-

regulation (1), and Articles 107j and 107k of Directive 2001/83/EC as

amended, 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.

(b) At any stage of the procedure laid down in Articles

107j to 107k of Directive 2001/83/EC as amended, the Commission

may request Member States in which the medicinal product is

authorised to take temporary measures immediately.

(4) (a)

Where the scope of the procedure, as determined in

accordance with sub-regulation (1), includes medicinal products

authorised in accordance with Regulation (EC) No 726/2004, the

Commission may, at any stage of the procedure initiated hereunder,

take temporary measures immediately in relation to those marketing

authorisations.

(b) The information referred to in this regulation may

relate to individual medicinal products or to a range of medicinal

products or a therapeutic class.

(c)

Where the scope of the procedure initiated under

this regulation 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 sub-regulation

(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.

(1) This regulation 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 of

Directive 2001/83/EC as amended, and which involve the collection

of safety data from patients or healthcare professionals.

(2) This regulation is without prejudice to national and

Community 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 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 twelve months of the end of data

collection.

(7) (a)

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.

(b) 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 of Directive 2001/83/EC as amended.

(c)

The obligation laid down in sub-regulation (2) 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 regulation 29.

(8) Regulations 59 to 62 shall apply exclusively to studies

referred to in sub-regulation (1) which are conducted pursuant to an

obligation imposed in accordance with Articles 21a or 22a of

Directive 2001/83/EC as amended.

(1) Before a study is conducted, the marketing Submission of

authorisation holder shall submit a draft protocol to the draft protocol.

Pharmacovigilance Risk Assessment Committee, except for studies to

be conducted in only one Member State (e.g. Malta) that requests the

study according to Article 22a of Directive 2001/83/EC. For such

studies, the marketing authorisation holder shall submit a draft

protocol to the Authority.

(2) Within sixty days of the submission of the draft protocol

the 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.

(3) (a)

The study may commence only when the written

endorsement from the Authority or the Pharmacovigilance Risk

Assessment Committee, as appropriate, has been issued.

(b) Where a letter of endorsement as referred to in sub-

regulation (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.

After a study has been commenced, any substantial Authorisation of

amendments to the protocol shall be submitted, before their amendments.

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.

(1)

Upon completion of the study, a final study report Finalisation of

the study.

shall be submitted to the national competent authority or the

Pharmacovigilance Risk Assessment Committee within twelve

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.

(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) (a)

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

Directive 2001/83/EC as amended, the Member States represented

within the coordination group shall agree a position on the matter

taking into account the recommendation referred to in sub-regulation

(1) and including a timetable for the implementation of the agreed

position.

(b) 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.

(c)

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.

(d) 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.

(e)

The agreement shall be made public on the

European medicines web- portal established in accordance with

Article 26 of Regulation (EC) No 726/2004.

(f)

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 of Directive

2001/83/EC as amended.

(g) 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.

The Pharmacovigilance Regulations, 2006 are hereby Revocation of

the

revoked.

Pharmacovigila

nce Regulations,

2006. L.N. 61 of 2006.

€1.98