PHARMACOVIGILANCE REGULATIONS

SUBSIDIARY LEGISLATION 458.35

PHARMACOVIGILANCE REGULATIONS

30th October, 2012

LEGAL NOTICE 369 of 2012, as amended by Legal Notices 352 of 2013,

305 of 2014 and 234 of 2022.

(1) The title of these regulations is the Pharmacovigilance

Regulations.

(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

"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" me ans a State w hich is a member o f 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

i d e n t i f y i ng , c h a r a c t e r i s i n g o r q u a n t i f y i n g a s a f e t y h a z a r d ,

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

t h e a s s e s s m e n t of t h e e ff e c t iv e ne s s o f t h o s e a c t i v it i e s a n d

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

s c i e n t i f i c a l l y, c o n s i d e r o p t i o n s f o r r i s k m i n i m i s a t i o n a n d

prevention and take regulatory action concerning the marketing

authorisation as necessary. A regular audit of its pharmacovigilance

s y s t e m sh al l b e ca r r i e d o u t a n d t h e r e s u l t s r e p o r t e d t o t h e

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)

o f Reg ula tio n (EC ) No 72 6/ 20 04 and sh all b e p erm an ent ly

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

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

d e l e g a t i n g M e m b e r St a t e a n d t h e A g e n c y s h a l l m a k e t h a t

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

Provided further that by way of derogation from the preceding

proviso, where the marketing authorisation is granted by the

competent authority of the United Kingdom in respect of Northern

Ireland, the qualified person referred to in paragraph (a) of this sub-

regulation may reside and operate in parts of the United Kingdom

other than Northern Ireland. This proviso shall not apply where the

marketing authorisation holder already has at its disposal a qualified

person who resides and operates in the European Union on 20 April

2022. (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

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

authorisation holder to operate a risk management system, as

referred 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

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 thirty days of receipt of the written notification of

the obligation.

On the basis of the written observations submitted by the

marketing authorisation holder, the Authority shall withdraw or

confirm the obligation. Where the 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.

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

Authority in order to guarantee their independence in the

performance 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.

Marketing authorisation holders shall pay fees for

pharmacovigilance obligations as levied under the Medicines

Authority (Fees) Regulations).

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

adverse reactions in the Community 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

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

consider reports of suspected adverse reactions received

electronically or by any other appropriate means from patients and

healthcare professionals.

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 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

electronically to the Eudravigilance database information on all

non-serious suspected adverse reactions that occur in the European

Union, 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

au thori sati on hol ders sh al l not be requi red to report to t he

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 t hey receive i n 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

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

medicinal product that are brought to its attention are made

available to the Eudravigilance database.

Unless there are justifiable grounds resulting from

pharmacovigilance activities, the Authority shall not impose any

additional obligations on marketing authorisation holders for the

reporting of suspected adverse reactions.

(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.

(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

r e g u l a t i o n 2 9 t o t h e A u t h o r i t y, t h e m e m b e r s o f t h e

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.

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

of marketing authorisations for medicinal products referred to 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

u p d a t e r e p o r t s s h a l l b e c o m m u n i c a t e d t o t h e A g e n c y ’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

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

are authorised only in one Member State and for which regulation

35 does not apply.

(1) 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 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

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

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 t he Comm unity 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

prepare an assessment report within sixty 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 thirty days of receipt of the assessment report, the

Member States and the marketing authorisation holder may submit

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

Following the receipt of the comments referred to in

regulation 44, the rapporteur or Member State shall within fifteen

da ys u p da te t h e a s s e s s m e nt r e p or t ta k in g i n to ac c o un t a ny

c o m m e n t s s u b m i t t e d , a n d f o r w a r d i t t o t h e A g e n c y ’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,

the Authority shall consider whether any action concerning the

marketing authorisation for the medicinal product concerned is

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

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 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

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.

(1) On the basis of the opinion of the Agency’s Committee

for Medicinal Products for Human Use referred to in 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

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

Commission adopts such decision, it may also adopt a decision

addressed to the Member States pursuant to Article 127a of

Directive 2001/83/EC as amended.

Regarding medicinal products authorised in accordance

with Directive 2001/83/EC as amended, the Authority 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 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)(a) The Authority 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 regulation

by informing the other Member States, the Agency and

the Commission where

(i)

it considers suspending or revoking a marketing

authorisation;

(ii) it considers prohibiting the supply of a

medicinal product;

(iii) it considers refusing the renewal of a marketing

authorisation; or

(iv) 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.

(b) The Authority 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 contra-

indication, 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.

The Authority or the Commission, as appropriate,

shall, when urgent action is considered necessary,

initiate the procedure provided for in this sub-

regulation in any of the cases referred to in this

regulation.

Where the procedure provided for in this regulation is

not initiated, for medicinal products authorised in

accordance with the procedures laid down in Chapter 4

of Title III of Directive 2001/83/EC, the case shall be

brought to the attention of the coordination group.

Article 31 of Directive 2001/83/EC shall be applicable

where the interests of the European Union are

involved.

(c) Where the procedure provided for in this regulation 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.

(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 shall apply. Otherwise, the safety concern shall be addressed by

the Member State concerned. The Agency or the Authority, as

applicable, shall make the 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

authorisation holder shall submit a draft protocol to the

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

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.

(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 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.

PHARMACOVIGILANCE

(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

a c c ou n t th e r e c o m m e nd a ti o n r e f e r r e d t o in s u b -

r e g u la t i o n ( 1 ) a nd i n c l u d i n g a t i m e t a b le f o r t he

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.