Medicines (Marketing Authorisation)

L.N. 373 of 2012

MEDICINES ACT

(CAP. 458)

Medicines (Marketing Authorisation)

(Amendment) 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 Medicines Citation, scope

(Marketing Authorisation) (Amendment) Regulations, 2012, and and

force.

these regulations shall be read and construed as one with the

Medicines (Marketing Authorisation) Regulations, hereinafter S.L. 458.34

referred to as "the principal regulations".

(2) The scope of these regulations is to transpose amendments

to Directive 2001/83/EC on the Community code relating to

medicinal products for human use, brought about by Directive 2010/

84/EU, as regards pharmacovigilance and Directive 2011/62/EU, as

regards the prevention of the entry into the legal supply chain of

falsified medicinal products.

(3) Paragraph (x) in the new regulation 5(1)(c) in regulation 5

hereof shall come into force on the 2nd January, 2013.

Sub-regulation (1) of regulation 2 of the principal Amends

regulation 2 of

regulations shall be amended as follows

the principal

regulations.

(a) immediately after the definition "Member State"

there shall be added the following new definitions

" "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;"; and

(b) immediately after the definition "risk-benefit plan"

there shall be added the following new definitions

" "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;".

Regulation 4 of the principal regulations shall be amended

as follows

(a)

paragraph (g) of sub-regulation (1) thereof shall be

substituted the following new paragraph

"(g) The marketing authorisation holder shall be

responsible for marketing the medicinal product and the

designation of a representative shall not relieve the

marketing authorisation holder of his legal responsibility.

The holder of a marketing authorisation for a medicinal

product and the distributors of the said medicinal product

actually placed on the market in Malta shall, within the

limits of their responsibilities, ensure appropriate and

continued supplies of that medicinal product to pharmacies

and persons authorised to supply medicinal products so

that the needs of patients in Malta are covered."; and

(b) immediately at the end of paragraph (b) of sub-

regulation (2) thereof, there shall be added the following new

paragraph

"The Authority may decide that

regulation 10(1) and (2) of the Medicinal

Products

(Labelling

and

Packaging)

Regulations and Article 63(1) and (2) of

Directive 2001/83/EC shall not apply to

medicinal

products

authorised

under

paragraph (a).".

Regulation 5 of the principal regulations shall be Substitutes

regulation 5 of

substituted by the following new regulation

the principal

regulations.

" Grant or

(1) A marketing authorisation

renewal of

may only be granted or renewed if the general

marketing

conditions applicable to authorisations and the

authorisation.

conditions set out under Directive 2001/83/EC

on the Community code relating to medicinal

products for human use and subsequent

amendments thereto, are fulfilled as follows

(a) an application for marketing

authorisation shall be made to the

Licensing Authority which shall refer

such application to the Authority for

processing;

(b) a marketing authorisation

may only be granted to an applicant

established in the Community;

(c)

the application shall be

accompanied by the following documents

and particulars to be submitted in

accordance with Annex I

(i) the name or corporate

name and permanent address of the

applicant and, where applicable, of

the manufacturer;

(ii) the name of the

medicinal product;

(iii) qualitative

and

quantitative particulars of all the

constituents of the medicinal

product, including the reference to

its international non-proprietary

name (INN) recommended by the

World Health Organisation, where

an INN for the medicinal product

exists, or a reference to the relevant

chemical name;

(iv) evaluation

of

the

potential environmental risks posed

by the medicinal product. This

impact shall be assessed and, on a

case-by-case

basis,

specific

arrangements to limit it shall be

envisaged;

(v) a description of the

manufacturing method;

(vi) therapeutic indications,

contra-indications

and

adverse

reactions;

(vii) posology,

pharma-

ceutical form, method and route of

administration and expected shelf

life;

(viii) reasons

for

any

precautionary and safety measures

to be taken for the storage of the

medicinal

product,

its

administration to patients and for

the disposal of waste products,

together with an indication of

potential risks presented by the

medicinal

product

for

the

environment;

(ix) description of the

control methods employed by the

manufacturer;

(x) a written confirmation

that the manufacturer of the

medicinal product has verified

compliance of the manufacturer of

the active substance with principles

and

guidelines

of

good

manufacturing

practice

by

conducting audits, in accordance

with regulation 5 of the Good

Manufacturing Practice in respect of

Medicinal

Products,

Active

Substances and Investigational

Medicinal Products for Human Use

Regulations.

The

written

confirmation shall contain a

reference to the date of the audit and

a declaration that the outcome of the

audit

confirms

that

the

manufacturing complies with the

principles and guidelines of good

manufacturing practice;

(xi) results

of

pharmaceutical (physico-chemical,

biological or microbiological) tests,

pre-clinical

(toxicological

and

pharmacological) tests, clinical

trials;

(xii) a summary of the

applicant’s

pharmacovigilance

system which shall include the

following elements

- proof

that

the

applicant has at his disposal a

qualified person responsible

for pharmacovigilance,

- the Member States

in which the qualified person

resides and carries out his

tasks,

- the contact details

of the qualified person,

- a statement signed

by the applicant to the effect

that the applicant has the

necessary means to fulfil the

tasks and responsibilities

listed in Title IX of Directive

2001/83/EC as amended,

- a reference to the

location

where

the

pharmacovigilance system

master file for the medicinal

product is kept;

(xiii) the risk management

plan describing the risk management

system which the applicant will

introduce for the medicinal product

concerned, together with a summary

thereof of the risk management

system which the applicant will

introduce;

(xiv) a statement to the

effect that clinical trials carried out

outside the European Union meet

the ethical requirements of the

Clinical Trials Regulations and of

Directive 2001/20/EC of the

European Parliament and of the

Council of the 4th April, 2001 on

the approximation of the laws,

regulations

and

administrative

provisions of the Member States

relating to the implementation of

good clinical practice in the conduct

of clinical trials on medicinal

products on human use;

(xv) a

summary,

in

accordance with regulation 8, of the

product characteristics, a mock-up

of the outer packaging, containing

the details provided for in the

Medicinal Products (Labelling and

Packaging) Regulations, and of the

immediate packaging of the

medicinal product, containing the

details provided for in those

regulations, together with a package

leaflet in accordance with those

same regulations;

(xvi) a document showing

that the manufacturer is authorised

in his own country to produce

medicinal products;

(xvii)

copies

of

the

following

- any authorisation,

obtained in another Member

State or in a third country, to

place the medicinal product

on the market, a summary of

the safety data including the

data contained in the periodic

safety update reports, where

available, and suspected

adverse reactions reports,

together with a list of those

Member States in which an

application for authorisation

submitted in accordance with

the provisions of Directive

2001/83/EC, as amended, is

under examination,

- the summary of the

product

characteristics

proposed by the applicant in

accordance with regulation 8

or

approved

by

the

competent authorities of the

Member State in accordance

with regulation 16 and the

package leaflet proposed in

accordance

with

the

Medicinal

Products

(Labelling and Packaging)

Regulations, or as approved

by the competent authorities

of the Member State in

accordance

with

the

Medicinal

Products

(Labelling and Packaging)

Regulations,

- details

of

any

decision

to

refuse

authorisation, whether in the

Community or in a third

country, and the reasons for

such a decision;

(xviii) a copy of any

designation of the medicinal product

as an orphan medicinal product

under Regulation (EC) No 141/2000

of the European Parliament and of

the Council of 16 December 1999

on orphan medicinal products,

accompanied by a copy of the

relevant Agency opinion.

(2) The documents and information

concerning the results of the pharmaceutical

and pre-clinical tests and the clinical trials

referred to in sub-regulation (1)(c)(x) shall be

accompanied by detailed summaries in

accordance with regulation 9.

(3) The risk management system

referred to in sub-regulation (1)(c)(xii) shall be

proportionate to the identified risks and the

potential risks of the medicinal product, and

the need for post-authorisation safety data.

(4) The information in sub-regulation

(1) shall be updated where and when

appropriate.".

5. Immediately after sub-regulation (2) of regulation 8 of the Amends

principal regulations, there shall be added the following new sub- regulation

the principal

regulation

regulations.

"(3) For medicinal products included in the list referred

to in Article 23 of Regulation (EC) No 726/2004, the summary

of product characteristics shall include the statement: "This

medicinal product is subject to additional monitoring". This

statement shall be preceded by the black symbol referred to in

Article 23 of Regulation (EC) No 726/2004 and followed by an

appropriate standardised explanatory sentence.

For all medicinal products, a standard text shall be

included expressly asking healthcare professionals to report any

suspected adverse reaction in accordance with the national

spontaneous reporting system. Different ways of reporting,

including electronic reporting, shall be available in compliance

with the second subparagraph of Article 107a(1) of Directive

2001/83/EC as amended.".

Regulation 16 of the principal regulations shall be Amends

regulation 16 of

amended as follows

the principal

regulations.

(a) sub-paragraphs (iii) and (iv) of paragraph (b) thereof

shall be substituted by the following new sub-paragraphs

"(iii) shall, without delay, make publicly

available the marketing authorisation together

with the package leaflet, the summary of the

product characteristics and any conditions

established in accordance with article 23 of the

Medicines Act and paragraph (c) and

regulation 17(a) and (b), and together with any

deadlines for the fulfilment of those conditions

for each medicinal product which they have

authorised;

(iv) shall draw up an assessment report

and make comments on the file as regards the

results of the pharmaceutical and pre-clinical

tests, the clinical trials, the risk management

system and the pharmacovigilance system of

the medicinal product concerned. The

assessment report shall be updated whenever

new information becomes available which is

important for the evaluation of the quality,

safety or efficacy of the medicinal product

concerned.";

(b) immediately at the end of paragraph (b) thereof,

there shall be added the following

"The Authority shall make the assessment report

publicly accessible without delay, together with the

reasons for their opinion, after deletion of any information

of a commercially confidential nature. The justification

shall be provided separately for each indication applied

for.

The public assessment report shall include a

summary written in a manner that is understandable to the

public. The summary shall contain, in particular, a section

relating to the conditions of use of the medicinal product.";

and

(c)

immediately after paragraph (b) thereof, there shall

be added the following new paragraph

"(c) In addition to the provisions laid down in

regulation 15, a marketing authorisation for a medicinal

product may be granted subject to one or more of the

following conditions

(i) to take certain measures for ensuring

the safe use of the medicinal product to be

included in the risk management system;

(ii)

to conduct post-authorisation safety

studies;

(iii) to comply with obligations on the

recording or reporting of suspected adverse

reactions which are stricter than those referred to

in Title IX of Directive 2001/83/EC as amended;

(iv) any other conditions or restrictions

with regard to the safe and effective use of the

medicinal product;

(v) the existence

of

an

adequate

pharmacovigilance system;

(vi) to conduct post-authorisation efficacy

studies where concerns relating to some aspects of

the efficacy of the medicinal product are identified

and can be resolved only after the medicinal

product has been marketed. Such an obligation to

conduct such studies shall be based on the

delegated acts adopted pursuant to Regulation 17

of these regulations, while taking into account the

scientific guidance referred to in Article 108a of

Directive 2001/83/EC as amended.

The marketing authorisation shall lay down

deadlines for the fulfilment of these conditions

where necessary.".

Regulation 17 of the principal regulations shall be Substitutes

regulation 17 of

substituted by the following new regulation

the principal

regulations.

"17. (a) In exceptional circumstances and following

consultation with the applicant, the marketing authorisation may

be granted subject to certain conditions, in particular relating to

the safety of the medicinal product, notification to the Authority

of any incident relating to its use, and action to be taken.

The marketing authorisation may be granted only

when the applicant can show that he is unable to provide

comprehensive data on the efficacy and safety of the medicinal

product under normal conditions of use, for objective, verifiable

reasons and it should be based on one of the grounds set out in

Schedule I.

Continuation of the marketing authorisation shall be

linked to the annual reassessment of these conditions.

(b)

After the granting of a marketing authorisation, the

Licensing Authority may impose an obligation on the marketing

authorisation holder

(i) to conduct a post-authorisation safety study if

there are concerns about the risks of an authorised

medicinal product. If the same concerns apply to more than

one medicinal product, the Authority shall, following

consultation with the Pharmacovigilance Risk Assessment

Committee, encourage the marketing authorisation holders

concerned to conduct a joint post-authorisation safety

study;

(ii) to conduct a post-authorisation efficacy study

when the understanding of the disease or the clinical

methodology indicate that previous efficacy evaluations

might have to be revised significantly. The obligation to

conduct the post-authorisation efficacy study shall be

based on the guidelines or Regulations published by the

Commission pursuant to Article 22b of Directive 2001/83/

EC as amended, while taking into account the scientific

guidance referred to in Article 108a of Directive 2001/83/

EC as amended.

The imposition of such an obligation shall be duly

justified, notified in writing, and shall include the objectives and

timeframe for submission and conduct of the study.

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 Licensing Authority shall

withdraw or confirm the obligation. Where the Licensing

Authority confirms the obligation, the marketing authorisation

shall be varied to include the obligation as a condition of the

marketing authorisation and the risk management system shall

be updated accordingly.

(c)

The marketing authorisation holder shall incorporate

any conditions referred to in paragraphs (a) and (b) and in

regulation 16(b), in his risk management system.

(d) The Member States shall inform the Agency of the

marketing authorisations that they have granted subject to

conditions pursuant to paragraphs (a) or (b) or in regulation

16(c).".

Regulation 18 of the principal regulations shall be

substituted by the following new regulation

"18. (1) After a marketing authorisation has been

granted, the marketing authorisation holder shall, in respect of

the methods of manufacture and control provided for in

regulation 5(1)(c)(v) and (ix), take account of scientific and

technical progress and introduce any changes that may be

required to enable the medicinal product to be manufactured and

checked by means of generally accepted scientific methods.

Those changes shall be subject to the approval of the

Licensing Authority.

(2) The marketing authorisation holder shall forthwith

provide the national competent authority with any new

information which might entail the amendment of the

particulars or documents referred to in regulation 5(1)(c),

regulation 7(1), (2) and (3), and regulation 8 , or Article 32(5),

or Annex I of Directive 2001/83/EC as amended.

In particular, the marketing authorisation holder shall

forthwith inform the national competent authority of any

prohibition or restriction imposed by the competent authorities

of any country in which the medicinal product is marketed and

of any other new information which might influence the

evaluation of the benefits and risks of the medicinal product

concerned. The information shall include both positive and

negative results of clinical trials or other studies in all

indications and populations, whether or not included in the

marketing authorisation, as well as data on the use of the

medicinal product where such use is outside the terms of the

marketing authorisation.

(3) The marketing authorisation holder shall ensure that

the product information is kept up to date with the current

scientific knowledge, including the conclusions of the

assessment and recommendations made public by means of the

European medicines web-portal established in accordance with

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

(4) In order to be able to continuously assess the risk-

benefit balance, the national competent authority may at any

time ask the marketing authorisation holder to forward data

demonstrating that the risk-benefit balance remains favourable.

The marketing authorisation holder shall answer fully and

promptly any such request.

The national competent authority may at any time ask the

marketing authorisation holder to submit a copy of the

pharmacovigilance system master file. The marketing

authorisation holder shall submit the copy at the latest seven

days after receipt of the request.

(5) After a marketing authorisation has been granted,

the holder of the authorisation shall inform the Authority of the

date of actual marketing of the medicinal product for human use

in Malta, taking into account the various presentations

authorised. The holder shall also notify the Authority if the

product ceases to be placed on the market in Malta, either

temporarily or permanently. Such notification shall, otherwise

than in exceptional circumstances, be made no less than two

months before the interruption in the placing on the market of

the product.

(6) Upon request by the Authority, particularly in the

context of pharmacovigilance, the marketing authorisation

holder shall provide it with all data relating to the volume of

sales of the medicinal product, and any data in his possession

relating to the volume of prescriptions.".

Regulation 19 of the principal regulations shall be

substituted by the following new regulation

"19. (1) Without prejudice to sub-regulations (5) and (6),

a marketing authorisation shall be valid for five years.

(2) The marketing authorisation may be renewed after

five years on the basis of a re-evaluation of the risk-benefit

balance by the Authority.

(3) To this end, the marketing authorisation holder shall

provide the Authority with a consolidated version of the file in

respect of quality, safety and efficacy, including the evaluation

of data contained in suspected adverse reactions reports and

periodic safety update reports submitted in accordance with

Title IX of Directive 2001/83/EC as amended, and information

on all variations introduced since the marketing authorisation

was granted, at least nine months before the marketing

authorisation ceases to be valid in accordance with sub-

regulation (1).

(4) Once renewed, the marketing authorisation shall be

valid for an unlimited period, unless the national competent

Authority decides, on justified grounds relating to

pharmacovigilance, including exposure of an insufficient

number of patients to the medicinal product concerned, to

proceed with one additional five-year renewal in accordance

with sub-regulation (2).

(5) Any authorisation granted by the Authority which

within three years of its granting is not followed by the actual

placing on the market of the authorised product in Malta shall

cease to be valid.

(6) When an authorised product previously placed on

the market in Malta is no longer actually present on the market

for a period of three consecutive years, the authorisation for that

product shall cease to be valid.

(7) The Authority may, in exceptional circumstances

and on public health grounds, grant exemptions from sub-

regulations (4) and (5) provided that such exemptions are duly

justified.".

Sub-regulation (4) of regulation 23 of the principal Amends

regulations shall be substituted by the following new sub-regulation: regulation

the principal

regulations.

"(4) The Member States, the Commission, the applicant

or the marketing authorisation holder shall, in specific cases

where the interests of the European Union are involved, refer

the matter to the Committee for application of the procedure

laid down in Articles 32, 33 and 34 of Directive 2001/83/EC as

amended before any decision is reached on an application for a

marketing authorisation or on the suspension or revocation of a

marketing authorisation, or on any other variation of the

marketing authorisation which appears necessary.

Where the referral results from the evaluation of data

relating to pharmacovigilance of an authorised medicinal

product, the matter shall be referred to the Pharmacovigilance

Risk Assessment Committee and Article 107j(2) of Directive

2001/83/EC may be applied. The Pharmacovigilance Risk

Assessment Committee shall issue a recommendation according

to the procedure laid down in Article 32 of Directive 2001/83/

EC as amended. The final recommendation shall be forwarded

to the Committee for Medicinal Products for Human Use or to

the coordination group, as appropriate, and the procedure laid

down in regulation 65 of the Pharmacovigilance Regulations,

2012, shall apply.

However, where urgent action is considered necessary, the

procedure laid down in regulations 60 and 65 of the

Pharmacovigilance Regulations, 2012, shall apply.".

Sub-regulation (2) of regulation 24 of the principal

Amends

regulation 24 of

regulations shall be deleted and sub-regulation (1) thereof shall be

the principal

renumbered as the whole regulation.

regulations.

€1.44